High penetration prodrug compositions of peptides and peptide-related compounds

ABSTRACT

The invention provides compositions of novel high penetration compositions (HPC) or high penetration prodrugs (HPP) of peptides and peptide-related compounds, which are capable of crossing biological barriers with higher penetration efficiency comparing to their parent drugs. The HPPs are capable of being converted to parent drugs or drug metabolites after crossing the biological barrier and thus can render treatments for the conditions that the parent drugs or metabolites can. Additionally, the HPPs/HPCs are capable of reaching areas that parent drugs may not be able to access or to render a sufficient concentration at the target areas and therefore render novel treatments. The HPPs/HPCs can be administered to a subject through various administration routes, e.g., locally delivered to an action site of a condition with a high concentration or systematically administered to a biological subject and enter the general circulation with a faster rate.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of International ApplicationNo. PCT/CN2010/072561, filed on May 10, 2010 and designating the U.S.,which is a continuation in part of and claims priority to U.S. patentapplication Ser. No. 12/463,374, filed on May 8, 2009, both of which areincorporated herein by reference. International Application No.PCT/CN2010/072561 and the present application both also claim priorityto Chinese Patent Application No. 200910135997.0, filed on May 8, 2009,which is incorporated herein by reference.

FIELD OF THE INVENTION

This invention relates to the field of pharmaceutical compositionscapable of penetrating one or more biological barriers and methods ofusing the pharmaceutical compositions for preventing, diagnosing and/ortreating condition or disease in human and animals that are treatable bypeptides or peptide-related compounds. The invention also relates tomethods of using the pharmaceutical compositions for screening new drugcandidates and methods of using the pharmaceutical compositions fordiagnosing a condition in a biological subject. A method for synthesisof HPPs/HPCs of peptides from N-terminal to C-terminal has beendeveloped.

BACKGROUND OF THE INVENTION

Peptides are polymers formed by linking amino acids with amide bonds.Peptides play various roles in a biological system. For example, peptidehormone is the largest group of hormones which modulate variousbiological processes in biological subjects. One nanogram ofhyrotropin-releasing hormone injected into a mouse increases the uptakeof iodide from the blood into the thyroid gland (R. L. Kisliuk,Principles of Medicinal Chemistry, 4^(th) Ed., W. O. Foye, et al. Eds.,Williams & Wilkins, 4^(th) Ed. 1995, p. 606). Tuftsin (Thr-Lys-Pro-Arg)stimulates phagocytosis and promotes antibody-dependent cellularcytotoxicity (V. A. Najjar, Mol. Cell. Biochem. 41, 1, 1981).Met-enkephaline (Tyr-Gly-Gly-Phe-Met) isolated from brain and smallintestine, acts as morphine does, in that it binds to the same receptorand has analgesic activity (J. R. Jaffe and W. R. Martin, inPharmacological Basis of Therapeutics, A. G. Gilman, et al., Eds., NewYork, Pergamon Press, 1990, p. 481). Other examples of peptide hormonesinclude, without limitation, oxytocin (Pierce et al., J. Biol. Chem.199, 929, 1952), vasopressin (Kamm et al., J. Am. Chem. Soc. 50, 573,1928), angiotensin (J. C. Garrison and M. J. Peach, in PharmacologicalBasis of Therapeutics, A. G. Gilman, et al., Eds., New York, PergamonPress, 1990, p. 749), gastrin (P. C. Emson and B. E. B. Sandberg, Annu,Rep. Med. Chem., 18, 31, 1983), somatostatin (A. V. Schally, et al.,Annu. Rev. Biochem., 47, 89, 1978), dynorphin (M. G. Weisskopf, et al.,Nature, 362, 423, 1993), endothelin (A. M. Doherty, J. Med. Chem., 35,1493, 1992), secretin (E. Jorper, Gastroenterology, 55, 157, 1968),calcitonin (M. V. L. Ray, et al., Biotechnology, 11, 64, 1993), insulin(F. Sanger, Br. Med. Bull., 16, 183, 1960), and competence stimulatingpeptide (CSP).

Another group of peptides are anti-microbial peptides which have beenfound to participate in innate immunity in a wide variety of organisms(Reddy et al. 2004). These peptides and others have attracted muchinterest due to their potential usefulness in treating infections,especially because they are often effective against bacterial strainsthat have become resistant to conventional antibiotics. One well-knownclass of anti-microbial peptides is the tachyplesins. Another class ofanti-microbial peptides is histatin peptides and the derivatives.Another class of antimicrobial peptide is hepcidin, which is alsoreferred as LEAP-1, for liver-expressed antimicrobial peptide.

Another group of peptides are calcium binding peptides that bindspecifically to calcified surfaces. One example of a calcium bindingpeptide comprises three amino acid repeat sequence (X-Y-Z)_(n), whereinX is aspartic acid, glutamic acid, asparagine, alanine or glutamine, Yand Z are alanine, serine, threonine, phosphoserine, orphosphothreonine, and n is a number from 1 to 40.

Unfortunately, peptides and peptide related compounds are rapidlyproteolysized by proteolytic enzymes. When peptides and peptide relatedcompounds are taken orally, they will be proteolysized in a few minutes.Other systematic administrations of peptides and peptide relatedcompounds are painful, and in many cases require frequent and costlyoffice visits to treat chronic conditions.

Therefore, a need exists in the art for novel compositions that arecapable of being delivered efficiently and effectively to the actionsite of a condition (e.g., a disease) to prevent, reduce or treatconditions as well as minimize adverse side effects.

SUMMARY OF THE INVENTION

One aspect of the invention is directed to a high penetration prodrug(HPP) or high penetration composition (HPC) comprising a functional unitcovalently linked to a transportational unit through a linker. The terms“HPP” and “HPC” are used alone or together herein and areinterchangeable unless specifically noted.

In certain embodiments, a functional unit of a HPP or HPC comprises amoiety of an agent, wherein the efficient and effective delivery of theagent to a biological subject and/or transportation of the agent acrossone or more biological barriers are/is desired.

In certain embodiments, a functional unit may be hydrophilic,lipophilic, or amphiphilic (i.e., both hydrophilic and lipophilic). Forexample, the lipophilic nature of a function unit may be inherent orachieved by converting the hydrophilic moieties of a functional unit tolipophilic moieties.

In certain embodiments, a functional unit of a HPP or HPC comprises amoiety of a peptide or peptide-related compound. A peptide-relatedcompound is a compound comprising a peptide structure, a peptidemetabolite, or an agent that can be metabolized into a peptide orpeptide metabolite after a HPP or HPC penetrates one or more biologicalbarriers. A peptide-related compound further includes a compound that isan analog or mimic of a peptide or a peptide metabolite, or an agentthat can be metabolized into an analogue or mimic of a peptide or apeptide metabolite, after a HPP or HPC penetrates one or more biologicalbarriers. Examples of peptides include, but are not limited to, peptidehormones (e.g. hyrotropin-releasing hormone, tuftsin (Thr-Lys-Pro-Arg),met-enkephaline (Tyr-Gly-Gly-Phe-Met), oxytocin, angiotensin, gastrin,somatostatin, dynorphin, endothelin, secretin, calcitonin, and insulin),enterostatins (e.g. Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg(VPGPR), and Ala-Pro-Gly-Pro-Arg (APGPR)), Melanocortin II(cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH), opioid peptides (e.g.Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-enkephalin(H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL, andH-Tyr-D-Ala-Gly-Phe-Leu-OH), neuropeptides, alkaloids, anti-inflammationpeptides, anti-microbial peptides (e.g. competence stimulating peptides,tachyplesins, histatin peptides and the derivatives), calcium bindingpeptides, regulation peptides, peptide vaccines, and peptide mimics(e.g. α-helix mimics and β-sheet mimics).

In certain embodiments, a transportational unit of a HPP or HPCcomprises a protonatable amine group that is capable of facilitating orenhancing the transportation or crossing of the HPP or HPC through oneor more biological barriers. In certain embodiments, the protonatableamine group is substantially protonated at the pH of the biologicalbarriers through which a HPP or HPC penetrates. In certain embodiments,the amine group can be reversibly protonated or deprotonated.

In certain embodiments, a linker covalently links the functional unit tothe transportational unit of a HPP or HPC and comprises a bond that iscapable of being cleaved after the HPP or HPC penetrates across one ormore biological barriers. The cleavable bond comprises, for example, acovalent bond, an ether, a thioether, an amide, an ester, a thioester, acarbonate, a carbamate, a phosphate or an oxime bond.

Another aspect of the invention relates to a pharmaceutical compositioncomprising at least one HPP or HPC of a peptide or peptide-relatedcompound and a pharmaceutically acceptable carrier.

Another aspect of the invention relates to a method for penetrating abiological barrier using a HPP or HPC of a peptide or peptide-relatedcompound.

Another aspect of the invention relates to a method for diagnosing theonset, development, or remission of a condition in a biological subjectby using a HPP or HPC of a peptide or peptide-related compound. Incertain embodiments, the HPP (or HPC) or the functional unit thereof isdetectable. In certain embodiments, the HPP/HPC or the functional unitof the HPP/HPC is inherently detectable, labeled with, or conjugated to,a detectable marker.

Another aspect of the invention relates to a method for screeningfunctional units, linkers, or transportational units for desiredcharacteristics.

Another aspect of the invention relates to a method for preventing,ameliorating, or treating a condition in a biological subject byadministering to the subject a composition in accordance with theinvention. In certain embodiments, the method relates to treating acondition in a subject treatable by peptides or peptide-relatedcompounds by administering to the subject a therapeutically effectiveamount of a peptide HPP/HPC, or a pharmaceutical composition thereof. Incertain embodiments, the conditions treatable by the method include,without limitation, pain, injuries, imflammation related conditions,microorganism related conditions, neuropeptide related conditions,hormone related conditions, tumor, abnormal blood pressure, obesity,brain injuries, allergy, male and female sexual dysfunction, metastasis,and other conditions relating to: tuftsin. antepartum, postpartum,anti-AD activities, antidiuretic activities, calcium homeostasis,melanocyte, hormone release, platelet aggregation, activities of CNS,and phagocytosis.

In certain embodiments, a pharmaceutical composition of a HPP/HPC isadministrated to a biological subject via various routes including, butnot limited to, oral, enteral, buccal, nasal, topical, rectal, vaginal,aerosol, transmucosal, epidermal, transdermal, dermal, ophthalmic,pulmonary, subcutaneous, and/or parenteral routes. In certain preferredembodiments, a pharmaceutical composition of HPP is administered orally,transdermally, topically, subcutaneously and/or parenterally.

In accordance with the advantages of the invention, without intending tobe limited by any particular mechanism, a therapeutically effectiveamount of a HPP or HPC can be administered locally to a site ofcondition with a less dosage at a higher concentration. The advantagesof the invention also include, for example, avoidance of systematicadministration, reduction of adverse effects (e.g., pain of injection,gastrointestinal/renal effects, and other side effect), and possiblenovel treatments due to high local concentration of a HPP, HPC or activeagent. The advantages further include, for example, systematicadministration of a HPP or HPC to a biological subject to achieve fasterand more efficient bioavailability, penetration of biological barriers(e.g., the blood brain barrier) which have been difficult to cross, andnew indications as a result of passing through biological barriers.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1: Structures of Structure 2, Structure 3, Structure 4, Structure5, Structure 6, Structure 7, Structure 8, Structure 9, Structure 10,Structure 11, Structure 12, Structure 13, Structure 14, Structure 15,Structure 16, Structure 17, Structure 18, Structure 19, Structure 20,Structure 21, Structure 22, Structure 23, Structure 24, Structure 25,Structure 26, Structure 27, Structure 28, Structure 29, Structure 30,Structure 31, Structure 32, Structure 33, Structure 34, Structure 35,Structure 36, Structure 37, Structure 38, Structure 39, Structure 40,Structure 41, Structure 42, Structure 43, Structure 44, Structure 45,Structure 46, Structure 47, Structure 48, Structure 49, Structure 50,Structure 51, Structure 52, Structure 53, Structure 54, Structure 55,Structure 56, Structure 57, Structure 58, Structure 59, Structure 60,Structure 61, Structure 62, Structure 63, Structure 64, Structure 65,Structure 66, Structure 67, Structure 68, Structure 69, Structure 70,Structure 71, Structure 72, Structure 73, Structure 74, Structure 75,Structure 76, Structure 77, Structure 78, Structure 79, Structure 80,Structure 81, Structure 82, Structure 83, Structure 84, Structure 85,Structure 86, Structure 87, Structure 88, Structure 89, Structure 90,Structure 91, Structure 92, Structure 93, Structure 94, Structure 95,Structure 96, Structure 97, Structure 98, Structure 99, Structure 100,Structure 101, Structure 102, Structure 103, Structure 104, Structure105, Structure 106, Structure 107, Structure 108, Structure 109,Structure 110, Structure 111, Structure 112, Structure 113, Structure114, Structure 115, Structure 116, Structure 117, Structure 118,Structure 119, Structure 120, Structure 121, Structure 122, Structure123, Structure 124, Structure 125, Structure 126, Structure 127,Structure 128, Structure 129, Structure 130, Structure 131, Structure132, Structure 133, Structure 134, Structure 135, Structure 136,Structure 137, Structure 138, Structure 139, Structure 140, Structure141, Structure 142, Structure 143, Structure 144, Structure 145,Structure 146, Structure 147, Structure 148, Structure 149, Structure150, Structure 151, Structure 152, Structure 153, Structure 154,Structure 155, Structure 156, Structure 157, Structure 158, Structure159, Structure 160, Structure 161, Structure 162, Structure 163,Structure 164, Structure 165, Structure 166, Structure 167, Structure168, Structure 169, Structure 170, Structure 171, Structure 172,Structure 173, Structure 174, Structure 175, Structure 176, Structure177, Structure 178, Structure 179, Structure 180, Structure 181,Structure 182, Structure 183, Structure 184, Structure 185, Structure186, Structure 187, Structure 188, Structure 189, Structure 190,Structure 191, Structure 192, Structure 193, Structure 194, Structure195, Structure 196, Structure 197, Structure 198, Structure 199,Structure 200, Structure 201, Structure 202, Structure 203, Structure204, Structure 205, Structure 206, Structure 207, Structure 208,Structure 209, Structure 210, Structure 211, Structure 212, Structure213, Structure 214, Structure 215, Structure 216, Structure 217,Structure 218, Structure 219, Structure 220, Structure 221, Structure222, Structure 223, Structure 224, Structure 225, Structure 226,Structure 227, Structure 228, Structure 229, Structure 230, Structure231, Structure 232, Structure 233, Structure 234, Structure 235,Structure 236, Structure 237, Structure 238, Structure 239, Structure240, Structure 241, Structure 242, Structure 243, Structure 244,Structure 245, Structure 246, Structure 247, Structure 248, Structure249, Structure 250, Structure 251, Structure 252, Structure 253,Structure 254, Structure 255, Structure 256, Structure 257, Structure258, Structure 259, Structure 260, Structure 261, Structure 262,Structure 263, Structure 264, Structure 265, Structure 266, Structure267, Structure 268, Structure 269, Structure 270, Structure 271,Structure 272, Structure 273, Structure 274, Structure 275, Structure276, Structure 277, Structure 278, Structure 279, Structure 280,Structure 281, Structure 282, Structure 283, Structure 284, Structure285, Structure 286, Structure 287, Structure 288, Structure 289,Structure 290, Structure 291, Structure 292, Structure 293, Structure294, Structure 295, Structure 296, Structure 297, Structure 298,Structure 299, Structure 300, Structure 301, Structure 302, Structure303, Structure 304, Structure 305, Structure 306, Structure 307,Structure 308, Structure 309, Structure 310, Structure 311, Structure312, Structure 313, Structure 314, Structure 315, Structure 316,Structure 317, Structure 318, Structure 319, Structure 320, Structure321, Structure 322, Structure 323, Structure 324, Structure 325,Structure 326, Structure 327, Structure 328, Structure 329, Structure330, Structure 331, Structure 332, Structure 333, Structure 334,Structure 335, Structure 336, Structure 337, Structure 338, Structure339, Structure 340, Structure 341, Structure 342, Structure 343,Structure 344, and Structure 345.

FIG. 2: Cumulative amounts ofAc-Tyr(Ac)-Gly-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂.HCl,HCl.(CH₃)₂NCH₂CH₂CH₂CO-Tyr(Ac)-Gly-Gly-Phe-Met-OCH₂CH₂CH₂CH₃,cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH₂CH₂N(CH₂CH₃)₂.HCl,cyclo(1,6)-H-Nle-Asp-His-D-Phe(4-I)-Arg(Ac)-Trp-Lys-NH₂.HCl,cyclo(1,6)—H-Nle-Asp-His-D-Ala(2-naphthyl)-Arg(NO₂)-Trp-Lys-NH₂.HCl,Ac-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.HCl,Ac-Tyr-Gly-Gly-Phe-Met-OH, cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH,cyclo(1,6)-Ac-Nle-Asp-His-D-Phe(4-I)-Arg-Trp-Lys-NH₂, andH-Val-Pro-Gly-Pro-Arg-OH, crossing isolated human skin tissue in Franzcells (n=5). In each case, the vehicle was pH 7.4 phosphate buffer (0.2M).

DETAILED DESCRIPTION OF THE INVENTION I. Structures of a HighPenetration Prodrug (HPP) or High Penetration Composition (HPC) of aPeptide or Peptide-Related Compound

One aspect of the invention is directed to a high penetration prodrug(HPP) or a high penetration composition (HPC). The term “highpenetration prodrug” or “HPP” or “high penetration composition” or “HPC”as used herein refers to a composition comprising a functional unitcovalently linked to a transportational unit through a linker.

A functional unit of a HPP/HPC which comprises a moiety of a parent drughas the properties of: 1) the delivery of the parent drug or the HPP/HPCinto a biological subject and/or the transportation of the parent drugacross a biological barrier are/is desired, 2) the HPP/HPC is capable ofpenetrating or crossing a biological barrier, and 3) the HPP/HPC iscapable of being cleaved so as to turn the moiety of a parent drug intothe parent drug or a metabolite of the parent drug.

In certain embodiments, a functional unit may be hydrophilic,lipophilic, or amphiphilic (hydrophilic and lipophilic). The lipophilicmoiety of the functional unit may be inherent or achieved by convertingone or more hydrophilic moieties of the functional unit to lipophilicmoieties. For example, a lipophilic moiety of a functional unit isproduced by converting one or more hydrophilic groups of the functionalunit to lipophilic groups via organic synthesis. Examples of hydrophilicgroups include, without limitation, carboxylic, hydroxyl, thiol, amine,phosphate/phosphonate and carbonyl groups. Lipophilic moieties producedvia the modification of these hydrophilic groups include, withoutlimitation, ethers, thioethers, esters, thioesters, carbonates,carbamates, amides, phosphates and oximes. In certain embodiments, afunctional unit is lipophilicized by acetylation. In certainembodiments, a functional unit is lipophilicized by esterification.

In certain embodiments, a parent drug of a HPP or HPC is selected fromthe group consisting of a peptide and a peptide-related compound. Themoiety of a peptide or peptide-related compound can be further convertedto a lipophilic moiety as described supra. As used herein, the term“peptide HPP/HPC” refers to a HPP or HPC of a peptide or peptide-relatedcompound. As used herein, the term “peptide HPPs/HPCs” refers to HPPs orHPCs of peptides or peptide-related compounds.

Peptides are well known in the art and are used in connection withvarious conditions. As used herein, a peptide refers to a sequence ofamino acids, wherein the sequence length is about 2 to about 50 aminoacids. For example, a peptide may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28,29, 30 or more amino acids. A peptide may comprise both D-amino acidsand/or L-amino acids.

An amino acid is a compound comprising both amine and carboxylfunctional groups. The carbon atom next to the carbonyl group of acarboxyl functional group is called the alpha-carbon. Amino acids with aside chain bonded to an alpha-carbon are referred to as alpha aminoacids. In amino acids that have an amino group and a carbon chainattached to the alph-carbon, the carbons are labeled in order as alpha,beta, gamma, and so on from the carbonyl carbon. An amino acid which hasthe amino group attached to the beta or gamma-carbon is referred to asbeta or gamma amino acid respectively, and so on.

An alpha amino acid is an amino acid which has amino and carboxylategroups bonded to the same carbon (the alpha carbon). The alpha carbon isone atom away from the carboxylate group. An alpha amino acid has astructure of Structure 1:

H₂NCHR′COOH  Structure 1

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

-   -   R′ is selected from the group consisting of substituted and        unsubstituted imidazolyl, substituted and unsubstituted        quanidino, substituted and unsubstituted carboxyl, substituted        and unsubstituted carboxamide, substituted and unsubstituted        alkyl, substituted and unsubstituted cycloalkyl, substituted and        unsubstituted heterocycloalkyl, substituted and unsubstituted        alkoxyl, substituted and unsubstituted alkylthio, substituted        and unsubstituted alkylamino, substituted and unsubstituted        alkylcarbonyl, substituted and unsubstituted perfluoroalkyl,        substituted and unsubstituted alkyl halide, substituted and        unsubstituted aryl, and substituted and unsubstituted heteroaryl        groups.

In certain embodiments, an amino acid has Structure 1, includingstereoisomers and pharmaceutically acceptable salts thereof, wherein:

-   -   R′ is selected from the group consisting of H—, CH₃,        HN═C(NH₂)—NH—(CH₂)₃—, H₂N—CO—CH₂—, HOOC—CH₂—, HS—CH₂—,        H₂N—CO—(CH₂)₂—, HS—(CH₂)₂—, HOOC—(CH₂)₂—, CH₃—CH₂-CH(CH₃)—,        (CH₃)₂CH—CH₂—, H₂N—(CH₂)₄—, CH₃—S—(CH₂)₂—, Phenyl-CH₂—, HO—CH₂—,        CH₃—CH(OH)—, 4-OH-Phenyl-CH₂—, CH₃—CH(CH₃)—,

and

derivatives thereof.

Examples of alpha amino acid include, without limitation, alanine (Ala),arginine (Arg), asparagine (Asn), aspartic acid (Asp), cysteine (Cys),glutamic acid (Glu), glutamine (Gln), glycine (Gly), histidine (His),homocysteine (Hcy), homoserine (Hse), isoleucine (Ile), leucine (Leu),lysine (Lys), methionine (Met), norleucine (Nle), norvaline (Nva),ornithine (Orn), penicillamine (Pen), phenylalanine (Phe), proline(Pro), serine (Ser), tyrosine (Thr), threonine (Trp), tryptophan (Tyr),valine (Val), pyroglutamic acid (pGLU), dinitrobenzylated lysine(dnp-LYS), phosphorylated threonine (pTHR), phosphorylated serine(pSER), phosphorylated tyrosine (pTYR), citrulline (CIT), N-methylatedalanine (nme-ALA), N-methylated isoleucine (nme-ILE), N-methylatedleucine (nme-LEU), N-methylated phenylalanine (nme-PHE), N-methylatedvaline (nme-VAL), N-methylated serine (nme-SER), N-methylated threonine(nme-THR), N-methylated tyrosine (nme-TYR), alpha amino-butyric acid(alpha-ABA), iso-aspartic acid (iso-ASP), acetylated lysine(Ac-LYS),2-methyl alanine (2-Me-ALA) and oxamic Acid (OXA).

A beta amino acid is an amino acid which has an amino group bonded tothe beta carbon which is the second carbons away from the carboxylategroup. Examples of beta amino acid include, without limitation,beta-alanine (β-Ala), beta-arginine (β-Arg), beta-asparagine (β-Asn),beta-aspartic acid (β-Asp), beta-cysteine (β-Cys), beta-glutamic acid(β-Glu), beta-glutamine (β-Gln), beta-histidine (β-His), beta-isoleucine(β-Ile), beta-leucine (β-Leu), beta-lysine (β-Lys), beta-methionine(β-Met), beta-phenylalanine (β-Phe), beta-proline (β-Pro), beta-serine(β-Ser), beta-tyrosine (β-Thr), beta-threonine (β-Trp), beta-tryptophan(β-Tyr) and beta-valine (β-Val).

A gamma amino acid is an amino acid which has an amino group bonded tothe gamma carbon which is the third carbons away from the carboxylategroup. Examples of gamma amino acid include, without limitation,gamma-glutamic acid (γ-GLU).

A peptide-related compound is a compound comprising a peptide structure,a peptide metabolite, or an agent that can be metabolized into a peptideor peptide metabolite after a peptide HPP/HPC penetrates one or morebiological barriers. A peptide-related compound further includes acompound that is an analog or mimic of a peptide or a peptidemetabolite, or an agent that can be metabolized into an analog or mimicof a peptide or a peptide metabolite, after a peptide HPP/HPC penetratesone or more biological barriers.

Examples of peptides and peptide-related compounds include, but are notlimited to, peptide hormones, neuropeptides, alkaloids, anti-microbialpeptides, anti-inflammation peptides, peptide toxins, regulationpeptides, calcium binding peptides, peptide vaccines and peptide mimics.

Peptide hormones are a class of peptides that have endocrine functionsin living animals. Peptide hormones are also identified in plants withimportant roles in cell-to-cell communication and plant defense. Peptidehormones are produced by various organs and tissues, e.g. heart(atrial-natriuretic peptide (ANP), atrial natriuretic factor (ANF)),pancreas (e.g. insulin, enterostatin, somatostatin), thegastrointestinal tract (cholecystokinin, gastrin (e.g. gastrin-34,gastrin-17 and gastrin-14), opioid peptides (e.g. Met-enkephalin,Leu-enkephalin, H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL, andH-Tyr-D-Ala-Gly-Phe-Leu-OH), cholecystokinin, secretin, motilin,vasoactive intestinal peptide, and enteroglucagon), adipose tissuestores (e.g. leptin), pituitary (e.g. luteinizing hormone,follicle-stimulating hormone, prolactin, adrenocorticotrophic hormone(ACTH), growth hormone, antidiuretic hormone, oxytocin, Melanocortin(e.g. Melanocortin II)), thyroid (e.g. calcitonin), spleen (e.g.tuftsin), brain (e.g. oxytocin, dynorphin), liver (e.g. angiotensin,angiotensin I and angiotensin II), endothelium (e.g. endothelin). Otherexamples of peptide hormone include, without limitation,thyrotropin-releasing hormone (TRH) and bradykinin.

Neuropeptides are peptides that are found in neural tissues that areinvolved in regulatory and signaling processes. Examples ofneuropeptides include, without limitation, neurotransimtters (e.g.N-Acetylaspartylglutamic acid, gastrin, cholecycstokinin, neuropeptideY, vasopressin, oxytocin, secretin, Substance P, somatostatin,vasoactive intestinal peptide (VIP), opioids (e.g. enkephalin,dynorphin, endorphin), galanin, neurotensin, TRH, atrial-natriureticpeptide.

Alkaloids are peptides usually from plants, fungi and some animals suchas shellfish. Alkaloids involved into defend of one organism fromconsuming by other organisms. Examples of alkaloids include, withoutlimitation, ergotamine, pandamine, dynorphin A-(1-8)-octapeptide, Nbeta-(D-Leu-D-Arg-D-Arg-D-Leu-D-Phe)-naltrexamine.

Anti-microbial peptides are peptides that inhibit the growth ofmicroorganisms, such as bacterial cells, fungi and protozoa. Examples ofanti-microbial peptides include, without limitation, bacitracin,gramicidin, valinomicin, competence stimulating peptides, tachyplesins,histatin peptides and the derivatives thereof,

Examples of anti-inflammation peptides are peptides having sequences ofSeq ID: 47, Seq ID: 48, and Seq ID: 49. (Table A)

Peptide toxins are peptides that are poisonous. Examples of peptidetoxins are palutoxins, agatoxins and curtatoxins.

Regulation peptides are peptides that regulate one or more processes inan biological subject. Examples of regulation peptides include, withoutlimitation, anserine and carnosine.

Other examples of peptides and peptide-related compounds include calciumbinding peptides, peptide vaccines [e.g. p45(IEIGLEGKGFEPTLE ALFGK) andp210 (KTTKQSFDLS VKAQY KKNKH)] and peptide mimics (e.g. α-helix mimicsand β-sheet mimics).

In certain embodiments, a functional unit of a peptide HPP/HPC comprisesa moiety having a structure of Structure F-1:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

each A₁-A_(m) is independently selected from the group consisting of2-naphthylalanine, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted alkoxyl, substituted andunsubstituted alkenyl, substituted and unsubstituted alkynyl,substituted and unsubstituted aryl, substituted and unsubstitutedheteroaryl residues and Structure A:

p of each A₁-A_(m) is an independently selected integer;

Z_(A-1) on each carbon of each A₁-A_(m), Z_(A-2) for each A₁-A_(m),Z_(NT), Z_(CT-1), and Z_(CT-2) are independently selected from the groupconsisting of H, CH₃, C₂H₅, C₃H₇, CF₃, C₂F₅, C₃F₇, substituted andunsubstituted alkyl, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide;

R_(A) on each carbon of each A₁-A_(m), R_(NT) and R_(CT) are selectedfrom the group consisting of H, substituted and unsubstitutedimidazolyl, substituted and unsubstituted quanidino, substituted andunsubstituted carboxyl, substituted and unsubstituted carboxamide,substituted and unsubstituted alkyl, substituted and unsubstitutedcycloalkyl, substituted and unsubstituted heterocycloalkyl, substitutedand unsubstituted alkoxyl, substituted and unsubstituted alkylthio,substituted and unsubstituted alkylamino, substituted and unsubstitutedalkylcarbonyl, substituted and unsubstituted perfluoroalkyl, substitutedand unsubstituted alkyl halide, substituted and unsubstituted aryl, andsubstituted and unsubstituted heteroaryl groups;

when a p of a A₁-A_(m) is an integer no less than 2, R_(A) on eachcarbon can be the same or different, Z_(A-1) on each carbon can be thesame or different;

an amino and a carboxyl functional group on a peptide chain may furtherform lactam bridges; and

a thiol group may further form disulfide bridges.

In certain embodiments, a functional unit of a peptide HPP/HPC comprisesa moiety having a structure selected from the group consisting ofStructure F-1 as defined supra, including stereoisomers andpharmaceutically acceptable salts thereof, wherein a R_(A) of a A₁-A_(m)may be further lipophilicized by acetylation or esterification.

In certain embodiments, a functional unit of a peptide HPP/HPC comprisesa moiety having a structure of Structure F-1 as defined supra, includingstereoisomers and pharmaceutically acceptable salts thereof, wherein mis selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, 12 . . . and 100.

In certain embodiments, the functional unit of a peptide HPP/HPCcomprises a moiety having a structure of Structure F-1 as defined supra,including stereoisomers and pharmaceutically acceptable salts thereof,wherein p is 1, 2, or 3.

In certain embodiments, the functional unit of a peptide HPP/HPCcomprises a moiety having a structure of Structure F-1 as defined supra,including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

p is 1, 2 or 3;

Z_(A-1) on each carbon of each A₁-A_(m), Z_(A-2) for each A₁-A_(m),Z_(NT), Z_(CT-1), and Z_(CT-2) are independently selected from the groupconsisting of H, CH₃, C₂H₅, C₃H₇, CF₃, C₂F₅, C₃F₇, substituted andunsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide;

R_(A),on each carbon of each A₁-A_(m), R_(NT) and R_(CT) are selectedfrom the group consisting of H, substituted and unsubstitutedimidazolyl, substituted and unsubstituted quanidino, substituted andunsubstituted carboxyl, substituted and unsubstituted carboxamide,substituted and unsubstituted alkyl, substituted and unsubstitutedcycloalkoxyl, substituted and unsubstituted heterocycloalkyl,substituted and unsubstituted alkoxyl, substituted and unsubstitutedalkylthio, substituted and unsubstituted alkylamino, substituted andunsubstituted alkylcarbonyl, substituted and unsubstitutedperfluoroalkyl, substituted and unsubstituted alkyl halide, substitutedand unsubstituted aryl, and substituted and unsubstituted heteroarylgroups;

when a p of a A₁-A_(m) is an integer no less than 2, R_(A) on eachcarbon can be the same or different, Z_(A-1) on each carbon can be thesame or different;

an amino and an carboxyl functional group on a peptide chain may furtherform lactam bridges; and

a thiol group may further form disulfide bridges.

As used herein, the term “pharmaceutically acceptable salt” means thosesalts of compounds of the invention that are safe for application in asubject. Pharmaceutically acceptable salts include salts of acidic orbasic groups present in compounds of the invention. Pharmaceuticallyacceptable acid addition salts include, but are not limited to,hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate,maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate,formate, benzoate, glutamate, methanesulfonate, ethanesulfonate,benzensulfonate, p-toluenesulfonate and pamoate (i.e.,1,11-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Certain compounds ofthe invention can form pharmaceutically acceptable salts with variousamino acids. Suitable base salts include, but are not limited to,aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, anddiethanolamine salts. For a review on pharmaceutically acceptable saltssee BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), incorporated herein byreference.

As used herein, unless specified otherwise, the term “alkyl” means abranched or unbranched, saturated or unsaturated, monovalent ormultivalent hydrocarbon group, including saturated alkyl groups, alkenylgroups and alkynyl groups. Examples of alkyl include, but are notlimited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, ethenyl,propenyl, butenyl, isobutenyl, pentenyl, hexenyl, heptenyl, octenyl,nonenyl, decenyl, undecenyl, dodecenyl, ethynyl, propynyl, butynyl,isobutynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl,undecynyl, dodecynyl, methylene, ethylene, propylene, isopropylene,butylene, isobutylene, t-butylene, pentylene, hexylene, heptylene,octylene, nonylene, decylene, undecylene and dodecylene. In certainembodiments, the hydrocarbon group contains 1 to 30 carbons. In certainembodiments, the hydrocarbon group contains 1 to 20 carbons. In certainembodiments, the hydrocarbon group contains 1 to 12 carbons.

As used herein, unless specified otherwise, the term “cycloalkyl” meansan alkyl which contains at least one ring and no aromatic rings.Examples of cycloalkyl include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl,cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. In certainembodiments, the hydrocarbon chain contains 1 to 30 carbons. In certainembodiments, the hydrocarbon group contains 1 to 20 carbons. In certainembodiments, the hydrocarbon group contains 1 to 12 carbons.

As used herein, unless specified otherwise, the term “heterocycloalkyl”means a cycloalkyl wherein at least one ring atom is a non-carbon atom.Examples of the non-carbon ring atom include, but are not limited to, S,O and N.

As used herein, unless specified otherwise, the term “alkoxyl” means analkyl, cycloalkyl or heterocycloalkyl, which contains one or more oxygenatoms. Examples of alkoxyl include, but are not limited to, —CH₂—OH,—OCH₃, —O-alkyl, -alkyl-OH, -alkyl-O-alkyl-, wherein the two alkyls canbe the same or different.

As used herein, unless specified otherwise, the term “alkyl halide”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore halogen atoms, wherein the halogen atoms can be the same ordifferent. The term “halogen” means fluorine, chlorine, bromine oriodine. Examples of alkyl halide include, but are not limited to,-alkyl-F, -alkyl-Cl, -alkyl-Br, -alkyl-I, -alkyl(F)—, -alkyl(Cl)—,-alkyl(Br)— and -alkyl(I)—.

As used herein, unless specified otherwise, the term “alkylthio” meansan alkyl, cycloalkyl or heterocycloalkyl, which contains one or moresulfur atoms. Examples of alkylthio include, but are not limited to,—CH₂—SH, —SCH₃, —S-alkyl, -alkyl-SH, -alkyl-5-alkyl-, wherein the twoalkyls can be the same or different.

As used herein, unless specified otherwise, the term “alkylamino” meansan alkyl, cycloalkyl or heterocycloalkyl, which contains one or morenitrogen atoms. Examples of alkylamino include, but are not limited to,—CH₂—NH, —NCH₃, —N(alkyl)-alkyl, —N-alkyl, -alkyl-NH₂, -alkyl-N-alkyland -alkyl-N(alkyl)-alkyl wherein the alkyls can be the same ordifferent.

As used herein, unless specified otherwise, the term “alkylcarbonyl”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore carbonyl groups. Examples of alkylcarbonyl group include, but arenot limited to, aldehyde group (—R—C(O)—H), ketone group (—R—C(O)—R′),carboxylic acid group (R—COOH), ester group (—R—COO—R′), carboxamide,(—R—COO—N(R′)R″), enone group (—R—C(O)—C(R)═C(R″)R″′), acyl halide group(—R—C(O)—X) and acid anhydride group (—R—C(O)—O—C(O)—R′), wherein R, R′,R″ and R′″ are the same or different alkyl, cycloalkyl, orheterocycloalkyl.

As used herein, unless specified otherwise, the term “perfluoroalkyl”means an alkyl, cycloalkyl or heterocycloalkyl, which contains one ormore fluoro group, including, without limitation, perfluoromethyl,perfluoroethyl, perfluoropropyl.

As used herein, unless specified otherwise, the term “aryl” means achemical structure comprising one or more aromatic rings. In certainembodiments, the ring atoms are all carbon. In certain embodiments, oneor more ring atoms are non-carbon, e.g. oxygen, nitrogen, or sulfur(“heteroaryl”). Examples of aryl include, without limitation, phenyl,benzyl, naphthalenyl, anthracenyl, pyridyl, quinoyl, isoquinoyl,pyrazinyl, quinoxalinyl, acridinyl, pyrimidinyl, quinazolinyl,pyridazinyl, cinnolinyl, imidazolyl, benzimidazolyl, purinyl, indolyl,furanyl, benzofuranyl, isobenzofuranyl, pyrrolyl, indolyl, isoindolyl,thiophenyl, benzothiophenyl, pyrazolyl, indazolyl, oxazolyl,benzoxazolyl, isoxazolyl, benzisoxazolyl, thiaxolyl, quanidino andbenzothiazolyl.

In certain embodiments, a transportational unit of a HPP/HPC comprises aprotonatable amine group that is capable of facilitating thetransportation or crossing of the HPP/HPC through one or more biologicalbarriers (e.g., >about 10 times, >about 50 times, >about 100times, >about 300 times, >about 500 times, >about 1,000 times fasterthan the parent drug). In certain embodiments, the protonatable aminegroup is substantially protonated at a physiological pH. In certainembodiments, the amine group can be reversibly protonated. In certainembodiments, the transportational unit may or may not be cleaved fromthe functional unit after the penetration of HPP/HPC through one or morebiological barriers. In certain embodiments, the transportational unitmay be from the functional unit, especially for peptides orpeptide-related compounds that have at least a free amino group. Incertain embodiments, when there are more than one protonatable group ina peptide or peptide-related compound, the peptide or peptide-relatedcompound is modified so that only one or two protonatable amine groupsare left, and all other protonatable groups are protected.

In certain embodiments, the protonatable amine group is selected fromthe group consisting of pharmaceutically acceptable substituted andunsubstituted primary amine groups, pharmaceutically acceptablesubstituted and unsubstituted secondary amine groups, andpharmaceutically acceptable substituted and unsubstituted tertiary aminegroups.

In certain embodiments, the protonatable amine group is selected fromthe group consisting of Structure Na, Structure Nb, Structure Nc,Structure Nd, Structure Ne, Structure Nf, Structure Ng, Structure Nh,Structure Ni, Structure Nj, Structure Nk, Structure Nl, Structure Nm,Structure Nn, Structure No, Structure Np, Structure Nq and Structure Nr:

including stereoisomers and pharmaceutically acceptable salts thereof.

As used herein, unless specified otherwise, each R₁₁-R₁₆ isindependently selected from the group consisting of nothing, H,CH₂COOR₁₁, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, P, NR₁₁, orany other pharmaceutically acceptable groups.

In certain embodiments, a linker covalently linking a functional unitand a transportational unit of a HPP/HPC comprises a bond that iscapable of being cleaved after the HPP/HPC penetrates across one or moreBBs. The cleavable bond comprises, for example, a covalent bond, anether, thioether, amide, ester, thioester, carbonate, carbamate,phosphate or oxime bond.

In certain embodiments, a peptide HPP/HPC has the following StructureL-1:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

F is a functional unit of a peptide HPP/HPC. Examples of F includeStructure F-1 as defined supra;

T_(C) and T_(N) are independently selected from the group consisting ofnothing, H, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted alkyloxyl, substitutedand unsubstituted alkenyl, substituted and unsubstituted alkynyl,substituted and unsubstituted aryl, substituted and unsubstitutedheteroaryl groups, Structure Na, Structure Nb, Structure Nc, StructureNd, Structure Ne, Structure Nf, Structure Ng, Structure Nh, StructureNi, Structure Nj, Structure Nk, Structure Nl, Structure Nm, StructureNn, Structure No, Structure Np, Structure Nq and Structure Nr as definedsupra;

L_(1C) and L_(1N) are independently selected from the group consistingof nothing, O, S, N(L₃), —N(L₃)—CH₂—O, —N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—,—O—CH(L₃)—O, and —S—CH(L₃)—O—;

L_(2C) and L_(2N) are independently selected from the group consistingof nothing, O, S, N(L₃), —N(L₃)—CH₂—O, —N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—,—O—CH(L₃)—O, —S—CH(L₃)—O—, —O-L₃-, —N-L₃-, —S-L₃-, —N(L₃)-L₅- and L₃;

L_(4C) and L_(4N) are independently selected from the group consistingof nothing, C═O, C═S,

for each L_(1C), L_(1N), L_(2C), L_(2N), L_(4C) and L_(4N), L₃ and L₆are independently selected from the group consisting of nothing, H,CH₂COOL₆, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, P, NL₃, or anyother pharmaceutically acceptable groups;

L₆ is independently selected from the group consisting of H, OH, Cl, F,Br, I, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, and substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, N, P(O)OL₆,CH═CH, C═C, CHL₆, CL₆L₇, aryl, heteroaryl, or cyclic groups; and

L₇ is independently selected from the group consisting of H, OH, Cl, F,Br, I, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, and substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, N, P(O)OL₆,CH═CH, C≡C, CHL₆, CL₆L₇, aryl, heteroaryl, or cyclic groups.

In certain embodiments, a HPP or HPC of a peptide or peptide-relatedcompound comprises the structure of Structure L-1, includingstereoisomers and pharmaceutically acceptable salts thereof, wherein:

-   -   F, L_(1C), L_(1N), L_(2C), L_(2N), T_(C) and T_(N) are defined        as supra; and L_(4C) and/or L_(4N) are/is C═O.

In certain embodiments, a HPP or HPC of a peptide or peptide-relatedcompound comprises the structure of Structure L-1, includingstereoisomers and pharmaceutically acceptable salts thereof, wherein:

F, L_(1C), L_(1N), L_(2C), L_(2N), L_(4C) and L_(4N) are defined assupra;

T_(C) is a transportational unit of a peptide HPP/HPC. For example,T_(C) is selected from the group consisting of Structure Na, StructureNb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, StructureNg, Structure Nh, Structure Ni, Structure Nj, Structure Nk, StructureNl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nqand Structure Nr as defined supra; and

T_(N) is selected from the group consisting of nothing, H, substitutedand unsubstituted alkyl, substituted and unsubstituted cycloalkyl, andsubstituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkyloxyl, substituted and unsubstituted alkenyl,substituted and unsubstituted alkynyl, substituted and unsubstitutedaryl, and substituted and unsubstituted heteroaryl groups.

In certain embodiments, a HPP or HPC of a peptide or peptide-relatedcompound comprises the structure of Structure L-1, includingstereoisomers and pharmaceutically acceptable salts thereof, wherein:

F, L_(1C), L_(1N), L_(2C), L_(2N), L_(4C) and L_(4N) are defined assupra;

T_(N) is a transportational unit of a peptide HPP/HPC. For example,T_(N) is selected from the group consisting of Structure Na, StructureNb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, StructureNg, Structure Nh, Structure Ni, Structure Nj, Structure Nk, StructureNl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nqand Structure Nr as defined supra; and

T_(C) is selected from the group consisting of nothing, H, substitutedand unsubstituted alkyl, substituted and unsubstituted cycloalkyl, andsubstituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkyloxyl, substituted and unsubstituted alkenyl,substituted and unsubstituted alkynyl, substituted and unsubstitutedaryl, and substituted and unsubstituted heteroaryl groups.

In certain embodiments, a peptide HPP/HPC has the following StructureL-2:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein: each A₁-A_(m) is independently selected from the groupconsisting of 2-naphthylalanine, substituted and unsubstituted alkyl,substituted and unsubstituted cycloalkyl, and substituted andunsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkynyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl residues, Structure A and Structure B:

p of each A₁-A_(m) is an independently selected integer;

T_(B) of each A₁-A_(m), T_(C) and T_(N) are independently selected fromthe group consisting of nothing, H, substituted and unsubstituted alkyl,substituted and unsubstituted cycloalkyl, and substituted andunsubstituted heterocycloalkyl, substituted and unsubstituted alkyloxyl,substituted and unsubstituted alkenyl, substituted and unsubstitutedalkynyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl groups, Structure Na, Structure Nb, StructureNc, Structure Nd, Structure Ne, Structure Nf, Structure Ng, StructureNh, Structure Ni, Structure Nj, Structure Nk, Structure Nl, StructureNm, Structure Nn, Structure No, Structure Np, Structure Nq and StructureNr as defined supra;

L_(1B) of each A₁-A_(m), L_(1C) and L_(1N) are independently selectedfrom the group consisting of nothing, O, S, —N(L₃)-, —N(L₃)—CH₂—O,—N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)-O, and —S—CH(L₃)—O—;

L_(2B) of each A₁-A_(m), L_(2C) and L_(2N) are independently selectedfrom the group consisting of nothing, O, S, —N(L₃)-, —N(L₃)—CH₂—O,—N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)-O, —S—CH(L₃)—O—, —O-L₃-, —N-L₃-,—S-L₃-, —N(L₃)-L₅- and L₃;

L_(4B) of each A₁-A_(m), L_(4C) and L_(4N) are independently selectedfrom the group consisting of C═O, C═S,

L₃ and L₅ are defined the same as supra;

Z_(A-1) on each carbon of each A₁-A_(m), Z_(A-2) for each A₁-A_(m),Z_(NT), Z_(CT-1) and Z_(CT-2) are independently selected from the groupconsisting of H, CH₃, C₂H₅, C₃H₇, CF₃, C₂F₅, C₃F₇, substituted andunsubstituted alkyl, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide;

R_(A) on each carbon of each A₁-A_(m), R_(B) on each carbon of eachA₁-A_(m), R_(NT) and R_(CT) are independently selected from the groupconsisting of substituted and unsubstituted imidazolyl, substituted andunsubstituted quanidino, substituted and unsubstituted carboxyl,substituted and unsubstituted carboxamide, substituted and unsubstitutedalkyl, substituted and unsubstituted cycloalkyl, and substituted andunsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted alkylcarbonyl, substituted andunsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, substituted and unsubstituted aryl, and substituted andunsubstituted heteroaryl groups;

when a p of a A₁-A_(m) is an integer no less than 2, R_(A) or R_(B) oneach carbon can be the same or different, Z_(A-1) on each carbon can bethe same or different;

an amino and an carboxyl functional group on a peptide chain may furtherform lactam bridges; and

a thiol group may further form disulfide bridges.

Examples of Peptide HPPs/HPCs.

In certain embodiments, a peptide HPP/HPC includes a compound having astructure selected from the group consisting of Structure 2, Structure3, Structure 4, Structure 5, Structure 6, Structure 7, Structure 8,Structure 9, Structure 10, Structure 11, Structure 12, Structure 13,Structure 14, Structure 15, Structure 16, Structure 17, Structure 18,Structure 19, Structure 20, Structure 21, Structure 22, Structure 23,Structure 24, Structure 25, Structure 26, Structure 27, Structure 28,Structure 29, Structure 30, Structure 31, Structure 32, Structure 33,Structure 34, Structure 35, Structure 36, Structure 37, Structure 38,Structure 39, Structure 40, Structure 41, Structure 42, Structure 43,Structure 44, Structure 45, Structure 46, Structure 47, Structure 48,Structure 49, Structure 50, Structure 51, Structure 52, Structure 53,Structure 54, Structure 55, Structure 56, Structure 57, Structure 58,Structure 59, Structure 60, Structure 61, Structure 62, Structure 63,Structure 64, Structure 65, Structure 66, Structure 67, Structure 68,Structure 69, Structure 70, Structure 71, Structure 72, Structure 73,Structure 74, Structure 75, Structure 76, Structure 77, Structure 78,Structure 79, Structure 80, Structure 81, Structure 82, Structure 83,Structure 84, Structure 85, Structure 86, Structure 87, Structure 88,Structure 89, Structure 90, Structure 91, Structure 92, Structure 93,Structure 94, Structure 95, Structure 96, Structure 97, Structure 98,Structure 99, Structure 100, Structure 101, Structure 102, Structure103, Structure 104, Structure 105, Structure 106, Structure 107,Structure 108, Structure 109, Structure 110, Structure 111, Structure112, Structure 113, Structure 114, Structure 115, Structure 116,Structure 117, Structure 118, Structure 119, Structure 120, Structure121, Structure 122, Structure 123, Structure 124, Structure 125,Structure 126, Structure 127, Structure 128, Structure 129, Structure130, Structure 131, Structure 132, Structure 133, Structure 134,Structure 135, Structure 136, Structure 137, Structure 138, Structure139, Structure 140, Structure 141, Structure 142, Structure 143,Structure 144, Structure 145, Structure 146, Structure 147, Structure148, Structure 149, Structure 150, Structure 151, Structure 152,Structure 153, Structure 154, Structure 155, Structure 156, Structure157, Structure 158, Structure 159, Structure 160, Structure 161,Structure 162, Structure 163, Structure 164, Structure 165, Structure166, Structure 167, Structure 168, Structure 169, Structure 170,Structure 171, Structure 172, Structure 173, Structure 174, Structure175, Structure 176, Structure 177, Structure 178, Structure 179,Structure 180, Structure 181, Structure 182, Structure 183, Structure184, Structure 185, Structure 186, Structure 187, Structure 188,Structure 189, Structure 190, Structure 191, Structure 192, Structure193, Structure 194, Structure 195, Structure 196, Structure 197,Structure 198, Structure 199, Structure 200, Structure 201, Structure202, Structure 203, Structure 204, Structure 205, Structure 206,Structure 207, Structure 208, Structure 209, Structure 210, Structure211, Structure 212, Structure 213, Structure 214, Structure 215,Structure 216, Structure 217, Structure 218, Structure 219, Structure220, Structure 221, Structure 222, Structure 223, Structure 224,Structure 225, Structure 226, Structure 227, Structure 228, Structure229, Structure 230, Structure 231, Structure 232, Structure 233,Structure 234, Structure 235, Structure 236, Structure 237, Structure238, Structure 239, Structure 240, Structure 241, Structure 242,Structure 243, Structure 244, Structure 245, Structure 246, Structure247, Structure 248, Structure 249, Structure 250, Structure 251,Structure 252, Structure 253, Structure 254, Structure 255, Structure256, Structure 257, Structure 258, Structure 259, Structure 260,Structure 261, Structure 262, Structure 263, Structure 264, Structure265, Structure 266, Structure 267, Structure 268, Structure 269,Structure 270, Structure 271, Structure 272, Structure 273, Structure274, Structure 275, Structure 276, Structure 277, Structure 278,Structure 279, Structure 280, Structure 281, Structure 282, Structure283, Structure 284, Structure 285, Structure 286, Structure 287,Structure 288, Structure 289, Structure 290, Structure 291, Structure292, Structure 293, Structure 294, Structure 295, Structure 296,Structure 297, Structure 298, Structure 299, Structure 300, Structure301, Structure 302, Structure 303, Structure 304, Structure 305,Structure 306, Structure 307, Structure 308, Structure 309, Structure310, Structure 311, Structure 312, Structure 313, Structure 314,Structure 315, Structure 316, Structure 317, Structure 318, Structure319, Structure 320, Structure 321, Structure 322, Structure 323,Structure 324, Structure 325, Structure 326, Structure 327, Structure328, Structure 329, Structure 330, Structure 331, Structure 332,Structure 333, Structure 334, Structure 335, Structure 336, Structure337, Structure 338, Structure 339, Structure 340, Structure 341,Structure 342, Structure 343, Structure 344, and Structure 345 as shownin FIG. 1, including stereoisomers and pharmaceutically acceptable saltsthereof, wherein:

R is selected from the group consisting of H, substituted andunsubstituted alkyl, substituted and unsubstituted cycloalkyl, andsubstituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkoxyl, substituted and unsubstituted alkylthio,substituted and unsubstituted alkylamino, substituted and unsubstitutedaryl, and substituted and unsubstituted heteroaryl residues;

X, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₂₁, X₂₂, X₂₃, X₂₄, X₂₅, X₂₆, and X₂₇are independently selected from the group consisting of C═O,C═S, COO,CSO, CH₂OCO, COOCH₂OCO, COCH₂OCO, CH₂—O—CH(CH₂OR₄)₂,CH₂—O—CH(CH₂OCOR₄)₂, SO₂, PO(OR), NO₂, NO, O, S, NR₅, and nothing;

R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, andR₂₇ are independently selected from the group consisting of H, O, NO₂,substituted and unsubstituted alkyl, substituted and unsubstitutedcycloalkyl, and substituted and unsubstituted heterocycloalkyl,substituted and unsubstituted alkoxyl, substituted and unsubstitutedalkylthio, substituted and unsubstituted alkylamino, substituted andunsubstituted alkenyl, substituted and unsubstituted alkynyl,substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl residues;

as used herein, unless specified otherwise, the term “HA” is nothing ora pharmaceutically acceptable acid, e.g. hydrochloride, hydrobromide,hydroiodide, nitric acid, sulfuric acid, bisulfic acid, phosphoric acid,phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid,lactic acid, salicylic acid, citric acid, tartaric acid, pantothenicacid, bitartaric acid, ascorbic acid, succinic acid, maleic acid,gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharicacid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid orpamoic acid; and

Ar is selected from the group consisting of phenyl, 2′-naphthyl,4-iodophenyl, substituted and unsubstituted aryl, and substituted andunsubstituted heteroaryl residues.

The corresponding parent peptides of peptide HPPs/HPCs having structureof Structures 2-343 are listed below in Tables A (I) and (II):

TABLE AParent peptide of peptide HPPs/HPCs having structure of Structures 2-345(I) SEQ Peptide ID HPP/HPC Parent drug NO. Peptide group FunctionStructure 2 Tyr-Gly-Gly-Phe-Met 1 Opioid peptide Analgesic activityMet-enkephalin Structure 3 Tyr-Gly-Gly-Phe-Met 1 Opioid peptideAnalgesic activity Met-enkephalin Structure 4 Tyr-Gly-Gly-Phe-Met 1Opioid peptide Analgesic activity Met-enkephalin Structure 5Tyr-Gly-Gly-Phe-Met 1 Opioid peptide Analgesic activity Met-enkephalinStructure 6 Tyr-Xaa-Gly-Phe-Leu 2 Opioid peptide Analgesic activityLeu-enkephalin Structure 7 Tyr-Xaa-Gly-Phe-Leu 2 Opioid peptideAnalgesic activity Leu-enkephalin Structure 8 Tyr-Xaa-Gly-Phe-Leu 2Opioid peptide Analgesic activity Leu-enkephalin Structure 9Tyr-Xaa-Gly-Phe-Leu 2 Opioid peptide Analgesic activity Leu-enkephalinStructure 10 Tyr-Ala-Gly-Xaa1-Xaa2 3 Opioid peptide Analgesic activitymimetic Structure 11 Tyr-Gly-Gly-Xaa1-Xaa2 4 Opioid peptideAnalgesic activity mimetic Structure 12 Tyr-Ala-Gly-Xaa1-Xaa2 3Opioid peptide Analgesic activity mimetic Structure 13Tyr-D-Ala-Phe-Gly-Tyr- 5 Opioid peptide Analgesic activity Pro-Serdermorphin Structure 14 Tyr-D-Ala-Phe-Gly-Tyr- 5 Opioid peptideAnalgesic activity Pro-Ser dermorphin Structure 15Tyr-D-Ala-Phe-Gly-Tyr- 5 Opioid peptide Analgesic activity Pro-Serdermorphin Structure 16 Tyr-D-Ala-Phe-Gly-Tyr- 5 Opioid peptideAnalgesic activity Pro-Ser dermorphin Structure 17 Thr-Lys-Pro-Arg 6Tuftsin Stimulate phagocytosis Structure 18 Thr-Lys-Pro-Arg 6 TuftsinStimulate phagocytosis Structure 19 Thr-Lys-Pro-Arg 6 Tuftsin Stimulatephagocytosis Structure 20 Thr-Lys-Pro-Arg 6 Tuftsin Stimulatephagocytosis Structure 21 Thr-Lys-Pro-Arg 6 Tuftsin Stimulatephagocytosis Structure 22 Thr-Lys-Pro-Arg 6 Tuftsin Stimulatephagocytosis Structure 23 Thr-Lys-Pro-Arg 6 Tuftsin Stimulatephagocytosis Structure 24 Tyr-Ala-Gly-Xaa1-Xaa2 3 Opioid peptideAnalgesic activity mimetic Structure 25 Tyr-Ala-Phe-Gly-Tyr- 7Opioid peptide Analgesic activity Pro-Ser dermorphin Structure 26Thr-Lys-Pro-Arg 6 Tuftsin Stimulate phagocytosis Structure 27Thr-Lys-Pro-Arg 6 Tuftsin Stimulate phagocytosis Structure 28Thr-Lys-Pro-Arg 6 Tuftsin Stimulate phagocytosis Structure 29Thr-Lys-Pro-Arg 6 Tuftsin Stimulate phagocytosis Structure 30Thr-Lys-Pro-Arg 6 Tuftsin Stimulate phagocytosis Structure 31Xaa3-Lys-Pro-Arg 8 retro inverso- Agonist of tuftsin tuftsinStructure 32 Xaa3-Lys-Pro-Arg 8 retro inverso- Agonist of tuftsintuftsin Structure 33 Xaa3-Lys-Pro-Arg 8 retro inverso-Agonist of tuftsin tuftsin Structure 34 Xaa3-Lys-Pro-Arg 8retro inverso- Agonist of tuftsin tuftsin Structure 35 Xaa3-Lys-Pro-Arg8 retro inverso- Agonist of tuftsin tuftsin Structure 36Xaa3-Lys-Pro-Arg 8 retro inverso- Agonist of tuftsin tuftsinStructure 37 Xaa3-Lys-Pro-Arg 8 retro inverso- Agonist of tuftsintuftsin Structure 38 Xaa3-Lys-Pro-Arg 8 retro inverso-Agonist of tuftsin tuftsin Structure 39 Xaa3-Lys-Pro-Arg 8retro inverso- Agonist of tuftsin tuftsin Structure 40 Xaa3-Lys-Pro-Arg8 retro inverso- Agonist of tuftsin tuftsin Structure 41Xaa3-Lys-Pro-Arg 8 retro inverso- Agonist of tuftsin tuftsinStructure 42 Xaa3-Lys-Pro-Arg 8 retro inverso- Agonist of tuftsintuftsin Structure 43 Nle-cyclo[Asp-His-D- 9 Melanocortin II melanocortinPhe-Arg-Trp-Lys] agonists male and female sexual dysfunctionStructure 44 Nle-cyclo[Asp-His-D- 9 Melanocortin II melanocortinPhe-Arg-Trp-Lys] agonists male and female sexual dysfunctionStructure 45 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 46 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 47 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 48 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 49 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 50 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 51 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 52 Val-Pro-Asp-Pro-Arg 10 Enterostatins Anti-obeseStructure 53 Val-Pro-Gly-Pro-Arg 11 Enterostatins Anti-obeseStructure 54 Val-Pro-Gly-Pro-Arg 11 Enterostatins Anti-obeseStructure 55 Val-Pro-Gly-Pro-Arg 11 Enterostatins Anti-obeseStructure 56 Val-Pro-Gly-Pro-Arg 11 Enterostatins Anti-obeseStructure 57 Val-Pro-Gly-Pro-Arg 11 Enterostatins Anti-obeseStructure 58 Val-Pro-Gly-Pro-Arg 11 Enterostatins Anti-obeseStructure 59 Ala-Pro-Gly-Pro-Arg 12 Enterostatins Anti-obeseStructure 60 Ala-Pro-Gly-Pro-Arg 12 Enterostatins Anti-obeseStructure 61 Ala-Pro-Gly-Pro-Arg 12 Enterostatins Anti-obeseStructure 62 Ala-Pro-Gly-Pro-Arg 12 Enterostatins Anti-obeseStructure 63 Ala-Pro-Gly-Pro-Arg 12 Enterostatins Anti-obeseStructure 64 Ala-Pro-Gly-Pro-Arg 12 Enterostatins Anti-obeseStructure 65 Tyr-Xaa4-Gly-Phe-Xaa4 13 Opioid peptide Analgesic activitymimetic Structure 66 Tyr-Xaa4-Gly-Phe-Xaa4 13 Opioid peptideAnalgesic activity mimetic Structure 67 Tyr-Xaa4-Gly-Phe-Xaa4 13Opioid peptide Analgesic activity mimetic Structure 68Tyr-Xaa4-Gly-Phe-Xaa4 13 Opioid peptide Analgesic activity mimeticStructure 69 Xaa5-Pro 14 Angiotensin II Anti- antagonists hypertensionStructure 70 Xaa5-Pro 14 Angiotensin II Anti- antagonists hypertensionStructure 71 Xaa24-Pro 15 Angiotensin II Anti- antagonists hypertensionStructure 72 Xaa24-Pro 15 Angiotensin II Anti- antagonists hypertensionStructure 73 Xaa24-Pro 15 Angiotensin II Anti- antagonists hypertensionStructure 74 Xaa24-Pro 15 Angiotensin II Anti- antagonists hypertensionStructure 75 Cys-Tyr-Ile-Gln-Asn- 16 Oxytocin Antepartum Cys-Pro-Leu-GlyPostpartum Structure 76 Cys-Tyr-Ile-Gln-Asn- 16 Oxytocin AntepartumCys-Pro-Leu-Gly Postpartum Structure 77 Cys-Tyr-Phe-Gln-Asn- 17Vasopressin Antidiuretic Cys-Pro-Arg-Gly Structure 78Cys-Tyr-Phe-Gln-Asn- 17 Vasopressin Antidiuretic Cys-Pro-Arg-GlyStructure 79 Cys-Tyr-Phe-Gln-Asn- 17 Vasopressin AntidiureticCys-Pro-Arg-Gly Structure 80 Cys-Tyr-Phe-Gln-Asn- 17 VasopressinAntidiuretic Cys-Pro-Arg-Gly Structure 81 Ser-Tyr-Ser-Met-Glu- 18adrenocorticotropic Regulation of His-Phe-Arg-Trp-Gly- hormoneactivity of CNS Lys-Pro-Val-Gly-Lys- Lys-Arg Structure 82Ser-Tyr-Ser-Met-Glu- 18 adrenocorticotropic Regulation ofHis-Phe-Arg-Trp-Gly- hormone activity of CNS Lys-Pro-Val-Gly-Lys-Lys-Arg Structure 83 Ser-Tyr-Ser-Met-Glu- 19 adrenocorticotropicRegulation of His-Phe-Arg-Trp-Gly- hormone activity of CNS Lys-Pro-ValStructure 84 Ser-Tyr-Ser-Met-Glu- 19 adrenocorticotropic Regulation ofHis-Phe-Arg-Trp-Gly- hormone activity of CNS Lys-Pro-Val Structure 85Ser-Tyr-Ser-Met-Glu- 20 adrenocorticotropic Regulation ofHis-Phe-Arg-Trp-Gly hormone activity of CNS Structure 86Ser-Tyr-Ser-Met-Glu- 20 adrenocorticotropic Regulation ofHis-Phe-Arg-Trp-Gly hormone activity of CNS Structure 87Met-Glu-His-Phe-Arg- 21 adrenocorticotropic Regulation of Trp-Glyhormone activity of CNS Structure 88 Met-Glu-His-Phe-Arg- 21adrenocorticotropic Regulation of Trp-Gly hormone activity of CNSStructure 89 Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 90Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 91Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 92Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 93Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 94Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 95Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 96Phe-Arg-Trp-Gly-Lys- 22 adrenocorticotropic Regulation ofPro-Val-Gly-Lys-Lys hormone activity of CNS Structure 97Lys-Pro-Val-Gly-Lys- 23 adrenocorticotropic Regulation ofLys-Arg-Arg-Pro-Val- hormone activity of CNS Lys-Val-Tyr-ProStructure 98 Lys-Pro-Val-Gly-Lys- 23 adrenocorticotropic Regulation ofLys-Arg-Arg-Pro-Val- hormone activity of CNS Lys-Val-Tyr-ProStructure 99 Lys-Pro-Val-Gly-Lys- 23 adrenocorticotropic Regulation ofLys-Arg-Arg-Pro-Val- hormone activity of CNS Lys-Val-Tyr-ProStructure 100 Lys-Pro-Val-Gly-Lys- 23 adrenocorticotropic Regulation ofLys-Arg-Arg-Pro-Val- hormone activity of CNS Lys-Val-Tyr-ProStructure 101 Arg-Pro-Val-Lys-Val- 24 adrenocorticotropic Regulation ofTyr-Pro-Asp-Gly-Ala- hormone activity of CNS Glu-Asp-Glu-Ser-Ala-Glu-Ala-Phe-Pro-Leu- Glu-Phe Structure 102 Arg-Pro-Val-Lys-Val- 24adrenocorticotropic Regulation of Tyr-Pro-Asp-Gly-Ala- hormoneactivity of CNS Glu-Asp-Glu-Ser-Ala- Glu-Ala-Phe-Pro-Leu- Glu-PheStructure 103 Arg-Pro-Val-Lys-Val- 24 adrenocorticotropic Regulation ofTyr-Pro-Asp-Gly-Ala- hormone activity of CNS Glu-Asp-Glu-Ser-Ala-Glu-Ala-Phe-Pro-Leu- Glu-Phe Structure 104 Arg-Pro-Val-Lys-Val- 24adrenocorticotropic Regulation of Tyr-Pro-Asp-Gly-Ala- hormoneactivity of CNS Glu-Asp-Glu-Ser-Ala- Glu-Ala-Phe-Pro-Leu- Glu-PheStructure 105 Val-Phe-Pro-Leu-Glu- 25 adrenocorticotropic Regulation ofPhe hormone activity of CNS Structure 106 Val-Phe-Pro-Leu-Glu- 25adrenocorticotropic Regulation of Phe hormone activity of CNSStructure 107 Lys-Leu-Val-Phe-Phe 26 Amyloid peptide Anti-ADStructure 108 Lys-Leu-Val-Phe-Phe 26 Amyloid peptide Anti-ADStructure 109 Lys-Leu-Val-Phe-Phe 26 Amyloid peptide Anti-ADStructure 110 Asp-Arg-Val-Tyr-Ile-His- 27 Angiotentensin Control bloodPro-Phe-His-Leu pressure Structure 111 Asp-Arg-Val-Tyr-Ile-His- 27Angiotentensin Control blood Pro-Phe-His-Leu pressure Structure 112Asp-Arg-Val-Tyr-Ile-His- 28 Angiotentensin Control blood Pro-Phepressure Structure 113 Asp-Arg-Val-Tyr-Ile-His- 28 AngiotentensinControl blood Pro-Phe pressure Structure 114 Asp-Arg-Val-Tyr-Ile-His- 29Angiotentensin Control blood Pro-Ala pressure Structure 115Asp-Arg-Val-Tyr-Ile-His- 29 Angiotentensin Control blood Pro-Alapressure Structure 116 Asp-Arg-Val-Tyr-Ile- 30 AngiotentensinControl blood Xaa7-Pro-Phe II agonist pressure Structure 117Asp-Arg-Val-Tyr-Ile- 30 Angiotentensin Control blood Xaa7-Pro-PheII agonist pressure Structure 118 Ser-Arg-Val-Tyr-Ile-His- 31Angiotentensin Control blood Pro-Phe II agonist pressure Structure 119Ser-Arg-Val-Tyr-Ile-His- 31 Angiotentensin Control blood Pro-PheII agonist pressure Structure 120 Asp-Arg-Val-Tyr-Ile-His- 32Angiotentensin Control blood Pro-Ile II agonist pressure Structure 121Asp-Arg-Val-Tyr-Ile-His- 32 Angiotentensin Control blood Pro IleII agonist pressure Structure 122 MeGly-Arg-Val-Tyr-Ile- 33Angiotentensin Control blood His-Pro-Phe II agonist pressureStructure 123 MeGly-Arg-Val-Tyr-Ile- 33 Angiotentensin Control bloodHis-Pro-Phe II agonist pressure Structure 124 MeGly-Arg-Val-Tyr-Ile- 34Angiotentensin Control blood His-Pro-Ile II antagonist pressureStructure 125 MeGly-Arg-Val-Tyr-Ile- 34 Angiotentensin Control bloodHis-Pro-Ile II antagonist pressure Structure 126 MeGly-Arg-Val-Tyr-Val-35 Angiotentensin Control blood His-Pro-Ala II agonist pressureStructure 127 MeGly-Arg-Val-Tyr-Val- 35 Angiotentensin Control bloodHis-Pro-Ala II agonist pressure Structure 128 Asp-Arg-Val-Tyr-Ile-His-36 Angiotentensin Control blood Pro-Thr II agonist pressureStructure 129 Asp-Arg-Val-Tyr-Ile-His- 36 Angiotentensin Control bloodPro-Thr II agonist pressure Structure 130 Asp-Arg-Val-Tyr-Ile-His- 37Angiotentensin Control blood Pro II agonist pressure Structure 131Asp-Arg-Val-Tyr-Ile-His- 37 Angiotentensin Control blood Pro II agonistpressure Structure 132 Val-Tyr-Ile-His-Pro-Phe 38 AngiotentensinControl blood II agonist pressure Structure 133 Arg-Val-Tyr-Ile-His-Pro-39 Angiotentensin Control blood Phe II agonist pressure Structure 134Arg-Val-Tyr-Ile-His-Pro- 39 Angiotentensin Control blood Phe II agonistpressure Structure 135 Glu-Gly-Val-Tyr-Val-His- 40 AngiotentensinControl blood Pro-Val II antagonist pressure Structure 136Xaa9-Tyr-Lys(Arg)-His- 41 Angiotentensin Control blood Pro-IleII AT2 receptor pressure Structure 137 Xaa9-Tyr-Lys(Arg)-His- 41Angiotentensin Control blood Pro-Ile II agonist pressure Structure 138Xaa9-Tyr-Lys(Arg)-His- 41 Angiotentensin Control blood Pro-IleII agonist pressure Structure 139 Arg-Leu-Cys-Arg-Ile- 42 AntimicrobialAntimicrobial Val-Val-Ile-Arg-Val-Cys- peptide Arg Structure 140Arg-Leu-Cys-Arg-Ile- 42 Antimicrobial AntimicrobialVal-Val-Ile-Arg-Val-Cys- peptide Arg Structure 141 Ala-Leu-Trp-Lys-Thr-43 Antimicrobial Antimicrobial Met-Leu-Lys-Lys-Leu- peptideGly-Thr-Met-Ala-Leu- His-Ala-Gly Structure 142 Ala-Leu-Trp-Lys-Thr- 43Antimicrobial Antimicrobial Met-Leu-Lys-Lys-Leu- peptideGly-Thr-Met-Ala-Leu- His-Ala-Gly Structure 143 Ala-Leu-Trp-Lys-Thr- 43Antimicrobial Antimicrobial Met-Leu-Lys-Lys-Leu- peptideGly-Thr-Met-Ala-Leu- His-Ala-Gly Structure 144 Ala-Leu-Trp-Lys-Thr- 43Antimicrobial Antimicrobial Met-Leu-Lys-Lys-Leu- peptideGly-Thr-Met-Ala-Leu- His-Ala-Gly Structure 145 Gly-Ile-Gly-Ala-Val-Leu-44 Antimicrobial Antimicrobial Lys-Val-Leu-Thr-Thr- peptideGly-Leu-Pro-Ala-Leu-Ile- Ser-Trp-Ile-Lys-Arg-Lys- Arg-Gln-GlnStructure 146 Gly-Ile-Gly-Ala-Val-Leu- 44 Antimicrobial AntimicrobialLys-Val-Leu-Thr-Thr- peptide Gly-Leu-Pro-Ala-Leu-Ile-Ser-Trp-Ile-Lys-Arg-Lys- Arg-Gln-Gln Structure 147Gly-Ile-Gly-Ala-Val-Leu- 44 Antimicrobial AntimicrobialLys-Val-Leu-Thr-Thr- peptide Gly-Leu-Pro-Ala-Leu-Ile-Ser-Trp-Ile-Lys-Arg-Lys- Arg-Gln-Gln Structure 148Gly-Ile-Gly-Ala-Val-Leu- 44 Antimicrobial AntimicrobialLys-Val-Leu-Thr-Thr- peptide Gly-Leu-Pro-Ala-Leu-Ile-Ser-Trp-Ile-Lys-Arg-Lys- Arg-Gln-Gln Structure 149 Gly-Met-Ala-Ser-Lys-45 Antimicrobial Antimicrobial Ala-Gly-Ala-Ile-Ala-Gly- peptideLys-Ile-Ala-Lys-Val-Ala- Leu-Lys-Ala-Leu Structure 150Gly-Met-Ala-Ser-Lys- 45 Antimicrobial AntimicrobialAla-Gly-Ala-Ile-Ala-Gly- peptide Lys-Ile-Ala-Lys-Val-Ala-Leu-Lys-Ala-Leu Structure 151 Gly-Met-Ala-Ser-Lys- 45 AntimicrobialAntimicrobial Ala-Gly-Ala-Ile-Ala-Gly- peptide Lys-Ile-Ala-Lys-Val-Ala-Leu-Lys-Ala-Leu Structure 152 Gly-Met-Ala-Ser-Lys- 45 AntimicrobialAntimicrobial Ala-Gly-Ala-Ile-Ala-Gly- peptide Lys-Ile-Ala-Lys-Val-Ala-Leu-Lys-Ala-Leu Structure 153 Gly-Met-Ala-Ser-Lys- 45 AntimicrobialAntimicrobial Ala-Gly-Ala-Ile-Ala-Gly- peptide Lys-Ile-Ala-Lys-Val-Ala-Leu-Lys-Ala-Leu Structure 154 Met-Arg-Gly-Phe-Val 46 AntibioticAntibiotic resistance resistance peptide Structure 155Met-Arg-Gly-Phe-Val 46 Antibiotic Antibiotic resistance resistancepeptide Structure 156 Met-Gln-Met-Lys-Lys- 47 Anti- Anti-inflammationVal-Leu-Asp-Ser inflammatory peptide Structure 157 Met-Gln-Met-Lys-Lys-47 Anti- Anti-inflammation Val-Leu-Asp-Ser inflammatory peptideStructure 158 Met-Gln-Met-Lys-Lys- 47 Anti- Anti-inflammationVal-Leu-Asp-Ser inflammatory peptide Structure 159 His-Asp-Met-Asn-Lys-48 Anti- Anti-inflammation Val-Leu-Asp-Leu inflammatory peptideStructure 160 His-Asp-Met-Asn-Lys- 48 Anti- Anti-inflammationVal-Leu-Asp-Leu inflammatory peptide Structure 161 Met-Gln-Met-Asn-Lys-49 Anti- Anti-inflammation Val-Leu-Asp-Ser inflammatory peptideStructure 162 Met-Gln-Met-Asn-Lys- 49 Anti- Anti-inflammationVal-Leu-Asp-Ser inflammatory peptide Structure 165 Arg-Pro-Pro-Gly-Phe-51 bradykinin Induction of Ser-Pro-Phe-Arg hypotension Structure 166D-Arg-Arg-Pro-Xaa26- 52 Bradykinin Control blood Gly-Phe-Ser-Phe-Leu-antagonist pressure Arg Structure 167 Arg-Pro-Pro-Gly-Phe- 53 BradykininControl blood Ser-Pro-Phe agonist pressure Structure 168Arg-Pro-Pro-Gly-Phe- 54 Bradykinin Control blood Ser-Pro-Leu antagonistpressure Structure 169 Arg-Pro-Pro-Gly-Phe- 55 Bradykinin Control bloodSer-D-Phe-Phe-Arg antagonist pressure Structure 170 Asp-Tyr-Met-Gly-Trp-56 Gastrin Control of food Met-Asp-Phe intake Structure 171Asp-Tyr-Met-Gly-Trp- 56 Gastrin Control of food Met-Asp-Phe intakeStructure 172 Gly-Trp-Thr-Leu-Asn- 57 Galanin Control of foodSer-Ala-Gly-Tyr-Leu- antagonist intake Leu-Gly-Pro-Pro-Pro-Gly-Phe-Ser-Pro-Phe- Arg Structure 173 Gly-Trp-Thr-Leu-Asn- 58 GalaninControl of food Ser-Ala-Gly-Tyr-Leu- antagonist intakeLeu-Gly-Pro-Arg-Pro- Lys-Pro-Gln-Gln-Trp- Phe-Trp-Leu-Leu Structure 174Gly-Trp-Thr-Leu-Asn- 58 Galanin Control of food Ser-Ala-Gly-Tyr-Leu-antagonist intake Leu-Gly-Pro-Arg-Pro- Lys-Pro-Gln-Gln-Trp-Phe-Trp-Leu-Leu Structure 175 Gly-Trp-Thr-Leu-Asn- 59 GalaninControl of food Ser-Ala-Gly-Tyr-Leu- antagonist intakeLeu-Gly-Pro-Gln-Gln- Phe-Phe-Gly-Leu-Met Structure 176Cys-Gly-Asn-Leu-Ser- 60 calcitonin Calcium Thr-Cys-Met-Leu-Gly-homeostasis Thr-Tyr-Thr-Gln-Asp- Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr- Ala-Ile-Gly-Val-Gly-Ala- Pro Structure 177Cys-Gly-Asn-Leu-Ser- 60 calcitonin Calcium Thr-Cys-Met-Leu-Gly-homeostasis Thr-Tyr-Thr-Gln-Asp- Phe-Asn-Lys-Phe-His-Thr-Phe-Pro-Gln-Thr- Ala-Ile-Gly-Val-Gly-Ala- Pro Structure 178Ala-Ala-Gly-Ile-Leu-Thr- 61 melanoma- Anti-tumor Val associatedantigen peptide Structure 179 Asn-Ala-Ala-Arg-Gln- 62 melanoma-Anti-tumor Gly-Phe-Leu-Asn-Thr- associated Leu-Val-Val-Leu-His-antigen peptide Arg-Ala-Gly-Ala-Arg Structure 180 Tyr-Met-Asp-Gly-Thr-63 melanoma- Anti-tumor Met-Ser-Gln-Val associated antigen peptideStructure 181 Ile-Ile-Ser-Ala-Val-Val- 64 melanoma- Anti-tumorGly-Ile-Leu associated antigen peptide Structure 182His-His-Leu-Gly-Gly- 65 Fibrinogen Inhibit platelet Ala-Lys-Gln-Ala-Gly-peptide aggregation Asp-Val Structure 183 His-His-Leu-Gly-Gly- 66Fibrinogen Inhibit platelet Ala-Lys-Gln-Ala-Gly- peptide aggregationAsp-Val Structure 184 Glu-His-Ile-Pro-Ala 67 Fibrinogen Inhibit plateletpeptide aggregation Structure 185 Arg-Gly-Asp-Val 68 FibrinogenInhibit platelet peptide aggregation Structure 186 Cyclo[Arg-Gly-Asp-D-69 Fibrinogen Inhibit platelet Phe-Val] peptide aggregationStructure 187 Arg-Gly-Asp-Ser 70 Fibrinogen Inhibit platelet peptideaggregation Structure 188 Thr-Asp-Val-Asn-Gly- 71 FibrinogenInhibit platelet Asp-Gly-Arg-His-Asp- peptide aggregation LeuStructure 189 Gly-Pro-Arg-Pro 72 Fibrinogen Inhibit platelet peptideaggregation Structure 190 D-Arg-Gly-Asp-Trp 73 FibrinogenInhibit platelet peptide aggregation Structure 191Trp-Thr-Val-Pro-Thr-Ala 74 Fibrinogen Inhibit platelet peptideaggregation Structure 192 Cys-Arg-Lys-Gln-Ala- 75 Laminin peptideInhibit metastasis Ala-Ser-Ile-Lys-Val-Ala- Val-Ser Structure 193Leu-Gly-Thr-Ile-Pro-Gly 76 Laminin peptide Inhibit metastasisStructure 194 Tyr-Ile-Gly-Ser-Arg 77 Laminin peptide Inhibit metastasisStructure 195 Ser-Ala-Gly-Thr 78 Vitronectin Inhibit metastasi peptideStructure 196 Cys-Arg-Lys-Gln-Ala- 79 Laminin peptide Inhibit metastasisAla-Ser-Ile-Lys-Val-Ala- Val-Ser Structure 197 Cys-Arg-Lys-Gln-Ala- 79Laminin peptide Inhibit metastasis Ala-Ser-Ile-Lys-Val-Ala- Val-SerStructure 198 Val-His-Phe-Phe-Lys- 80 EAE inducing Control allergicAsn-Ile-Val-Thr-Ala-Arg- peptides encephalomyelitis Thr-ProStructure 199 Val-His-Phe-Phe-Lys- 80 EAE inducing Control allergicAsn-Ile-Val-Thr-Ala-Arg- peptides encephalomyelitis Thr-ProStructure 200 Cys-Ser-Cys-Ser-Ser- 81 Endothelin Control bloodLeu-Met-Asn-Lys-Glu- peptide pressure Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp Structure 201 Cys-Ser-Cys-Ser-Ser- 81 EndothelinControl blood Leu-Met-Asn-Lys-Glu- peptide pressure Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp Structure 202 Ala-Ser-Ala-Ser-Ser- 82 EndothelinControl blood Leu-Met-Asp-Lys-Glu- peptide pressure Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp Structure 203 Ala-Ser-Ala-Ser-Ser- 82 EndothelinControl blood Leu-Met-Asp-Lys-Glu- peptide pressure Ala-Val-Tyr-Phe-Ala-His-Leu-Asp-Ile-Ile-Trp Structure 204 Leu-Met-Asp-lys-Glu- 83 EndothelinControl blood Ala-Val-Tyr-Phe-Ala- peptide pressureHis-Leu-Asp-Ile-Ile-Trp Structure 205 Asp-Glu-Glu-Ala-Val- 84 EndothelinControl blood Tyr-Phe-Ala-His-Leu- peptide pressure Asp-Ile-Ile-TrpStructure 206 Cys-Val-Tyr-Phe-Cys- 85 Endothelin Control bloodHis-Leu-Asp-Ile-Ile-Trp peptide pressure antagonist Structure 207Cyclo(D-Trp-D-Asp-Pro- 86 Endothelin Control blood D-Val-Leu) peptidepressure antagonist Structure 208 Xaa13-Leu-Asp-Ile-Ile- 87 EndothelinControl blood Trp peptide pressure antagonist Structure 209Cys-Ser-Cys-Ser-Ser- 88 Endothelin Control blood Trp-Leu-Asp-Lys-Glu-peptide pressure Cys-Val-Tyr-Phe-Cys- His-Leu-Asp-Ile-Ile-TrpStructure 210 Cys-Ser-Cys-Ser-Ser- 88 Endothelin Control bloodTrp-Leu-Asp-Lys-Glu- peptide pressure Cys-Val-Tyr-Phe-Cys-His-Leu-Asp-Ile-Ile-Trp Structure 211 Cys-Thr-Cys-Phe-Thr- 89 EndothelinControl blood Tyr-Lys-Asp-Cys-Val- peptide pressure Tyr-Tyr-Cys-His-Leu-Asp-Ile-Ile-Trp Structure 212 Cys-Thr-Cys-Phe-Thr- 89 EndothelinControl blood Tyr-Lys-Asp-Cys-Val- peptide pressure Tyr-Tyr-Cys-His-Leu-Asp-Ile-Ile-Trp Structure 213 Val-Gln-Gly-Glu-Glu- 90 Growth factorsControl growth Ser-Asn-Asp-Lys Structure 214 Val-Gln-Gly-Glu-Glu- 90Growth factors Control growth Ser-Asn-Asp-Lys Structure 215Asp-Val-Val-Asp-Ala- 91 Growth factors Control growthAsp-Glu-Tyr-Leu-Ile- Pro-Gln Structure 216 Asp-Ala-Asp-Glu-Tyr- 92Growth factors Control growth Leu Structure 217 Xaa14-Met-His-Ile-Glu-93 Growth factors Control growth Ser-Leu-Asp-Ser-Tyr- Thr-Xaa14Structure 218 Tyr-Arg-Ser-Arg-Lys- 94 Growth factors Control growthTyr-Ser-Ser-Trp-Tyr Structure 219 Ala-Leu-Leu-Glu-Thr- 95 Growth factorsControl growth Tyr-Cys-Ala-Thr-Pro- Ala-Lys-Ser-Glu Structure 220Ala-Leu-Leu-Glu-Thr- 95 Growth factors Control growthTyr-Cys-Ala-Thr-Pro- Ala-Lys-Ser-Glu Structure 221 His-D-Trp-Ala-Trp-D-96 Growth Control growth Phe-Lys hormone hormone releasing peotideStructure 222 His-D-Trp-Ala-Trp-D- 96 Growth Control growth Phe-Lyshormone hormone releasing peotide Structure 223 His-D-Trp-D-Lys-Trp-D-97 Growth Control growth Phe-Lys hormone hormone releasing peotideStructure 224 His-D-Trp-D-Lys-Trp-D- 97 Growth Control growth Phe-Lyshormone hormone releasing peotide Structure 225 His-D-Trp-D-Lys-Trp-D-97 Growth Control growth Phe-Lys hormone hormone releasing peotideStructure 226 Xaa15-His-Trp-Ser-Tyr- 98 Luteinizing ControlGly-Leu-Arg-Pro-Gly hormone luteinizing releasing hormone hormoneStructure 227 Xaa15-His-Trp-Ser-Tyr- 98 Luteinizing ControlGly-Leu-Arg-Pro-Gly hormone luteinizing releasing hormone hormoneStructure 228 Xaa15-His-Trp-Ser-Tyr- 99 Luteinizing ControlGly-Leu-Arg-Pro hormone luteinizing releasing hormone hormone agonistStructure 229 Xaa15-His-Trp-Ser-Tyr- 99 Luteinizing ControlGly-Leu-Arg-Pro hormone luteinizing releasing hormone hormone agonistStructure 230 Xaa15-His-Trp-Ser-His- 100 Luteinizing ControlAsp-Trp-Lys-Pro-Gly hormone luteinizing releasing hormone hormoneagonist Structure 231 Ala-Gly-Cys-Lys-Asn- 101 somatostatinControl growth Phe-Phe-Trp-Lys-Thr- hormone Phe-Thr-Ser-CysStructure 232 Ala-Gly-Cys-Lys-Asn- 101 somatostatin Control growthPhe-Phe-Trp-Lys-Thr- hormone Phe-Thr-Ser-Cys Structure 233Ala-Gly-Cys-Lys-Asn- 101 somatostatin Control growthPhe-Phe-Trp-Lys-Thr- hormone Phe-Thr-Ser-Cys Structure 234Xaa15-Leu-Asn-Phe- 102 neuropeptide Regulator of Ser-Ala-Gly-Trp energymetabolism Structure 235 Xaa15-Leu-Asn-Phe- 103 neuropeptideRegulator of Ser-Thr-Gly-Trp energy metabolism Structure 236Xaa15-Leu-Asn-Phe- 103 neuropeptide Regulator of Ser-Thr-Gly-Trp energymetabolism Structure 237 Glu-Ala-Leu-Glu-Leu- 104 neuropeptideBrain injury Ala-Arg-Gly-Ala-Ile-Phe- Gln-Ala Structure 238Ser-Tyr-Ser-Met-Glu- 105 Melanocyte Control His-Phe-Arg-Trp-Gly-stimulating melanocyte Lys-Pro-Val hormones Structure 239Ser-Tyr-Ser-Met-Glu- 105 Melanocyte Control His-Phe-Arg-Trp-Gly-stimulating melanocyte Lys-Pro-Val hormones Food intake Structure 240Cys-Nle-Arg-His-Xaa17- 106 Melanocyte Control Arg-Trp-Gly-Cysstimulating melanocyte hormones Food intake Structure 241Cys-Glu-His-D-Xaa17- 107 Melanocyte Control Arg-Trp-Gly-Cys-Pro-stimulating melanocyte Pro-Lys-Asp hormones Food intake Structure 242Nle-Asp-His-Phe-Arg- 108 Melanocyte Control Trp-Lys stimulatingmelanocyte hormones Food intake dysfunction Structure 243Nle-Asp-His-Xaa17- 109 Melanocyte Control Arg-Trp-Lys stimulatingmelanocyte hormones Food intake Structure 244 Nle-Gln-His-D-Phe-Arg- 110Melanocyte Control D-Trp-Gly stimulating melanocyte hormones Food intakeAnti-inflammation Structure 245 Nle-Lys-His-D-Phe-Arg- 110 MelanocyteControl D-Trp-Gly stimulating melanocyte hormones Food intakeAnti-inflamation Structure 246 Nle-Lys-His-D-Phe-Arg- 110 MelanocyteControl D-Trp-Gly stimulating melanocyte hormones Food intakeAnti-inflamation Structure 247 Nle-Asp-His-Xaa17-Arg- 111 MelanocyteControl Trp-Lys stimulating melanocyte hormones Food intakemale and female sexual dysfunction Structure 248 Nle-Asp-His-D-Phe-Arg-112 Melanocyte Control Trp-Lys stimulating melanocyte hormonesFood intake male and female sexual dysfunction Structure 249Trp-Ala-Gly-Gly-Asp- 113 Sleep inducing Sleep inducing Ala-Ser-Gly-Glupeptide Structure 344 Arg-Lys-Asp-Val-Tyr 172 immunostimulantenhances the production of thymic T cells and may help restoreimmunocompetence in immunosuppressed subjects Structure 345Arg-Lys-Asp-Val-Tyr 172 immunostimulant enhances the production ofthymic T cells and may help restore immunocompetence in immunosuppressedsubjects (II) Peptide SEQ HPP/HPC Parent Drug ID NO. Structure163Tyr-Thr-Ser-Leu-Ile-His-Ala-Leu-Ile-Gln-Gln-Ser-Gln-Asn- 50Gln-Gln-Gln-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe Structure164Tyr-Thr-Ser-Leu-Ile-His-Ala-Leu-Ile-Gln-Gln-Ser-Gln-Asn- 50Gln-Gln-Gln-Lys-Asn-Glu-Gln-Glu-Leu-Leu-Glu-Leu-Asp-Lys-Trp-Ala-Ser-Leu-Trp-Asn-Trp-Phe Structure250 Phe-Met-Arg-Phe 114Structure251 Xaa15-Asp-Pro-Phe-Leu-Arg-Phe 115 Structure252Cys-Nle-Arg-His-Xaa17-Arg-Trp-Gly-Cys 116 Structure253Glu-Ala-Leu-Glu-Leu-Ala-Arg-Gly-Ala-Ile-Phe-Gln-Ala 117 Structure254Glu-Ala-Leu-Glu-Leu-Ala-Arg-Gly-Ala-Ile-Phe-Gln-Ala 117 Structure255Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe 118 Structure256Tyr-Ile-Asn-Leu-Ile-Tyr-Arg-Leu-Arg-Tyr 119 Structure257His-Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr 120 Structure258Tyr-Ile-Asn-Leu-Ile-Thr-Arg-Gln-Arg-Tyr 121 Structure259Ile-Asn-Pro-Ile-Tyr-Arg-Leu-Arg-Tyr 122 Structure260Arg-Phe-Met-Trp-Met-Lys 123 Structure261 Tyr-D-Ala-Phe-Asp-Val-Val-Gly124 Structure262 Tyr-D-Ala-Phe-Glu-Val-Val-Gly 125 Structure263Tyr-Xaa4-Gly-Phe-Xaa4 126 Structure264 Tyr-Xaa4-Gly-Xaa19-Xaa4 127Structure265 Tyr-Pro-Trp-Thr-Gln-Arg-Phe 128 Structure266Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe 129 Structure267 Tyr-Pro-Phe-Phe 130Structure268 Tyr-Pro-Trp-Phe 131 Structure269Xaa25-Tyr-Phe-Gln-Asn-Cys-Pro-D-Arg-Gly 132 Structure270Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly 133 Structure271Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Lys-Gly 133 Structure272 Tyr-Glu-Glu-Ile-Glu134 Structure273 Tyr-Glu-Glu-Ile-Glu 134 Structure274Tyr-Glu-Glu-Ile-Glu 134 Structure275 Tyr-Glu-Glu-Ile-Glu 134Structure276 Thr-Ser-Thr-Glu-Pro-Gln-Tyr-Gln-Pro-Gly-Glu-Asn-Leu 135Structure277 Tyr-Glu 136 Structure278 Leu-Arg-Arg-Ala-Ser-Leu-Gly 137Structure279 Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val-His-138 Glu-Val-Lys-Asn Structure280Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val-His- 138Glu-Val-Lys-Asn Structure281Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val-His- 138Glu-Val-Lys-Asn Structure282Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val-His- 138Glu-Val-Lys-Asn Structure283Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val 139 Structure284Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val 139 Structure285Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val 139 Structure286Arg-Phe-Ala-Arg-Lys-Gly-Ser-Leu-Arg-Gln-Lys-Asn-Val 140 Structure287Arg-Phe-Ala-Arg-Lys-Gly-Ser-Leu-Arg-Gln-Lys-Asn-Val 140 Structure288Arg-Phe-Ala-Arg-Lys-Gly-Ala-Leu-Arg-Gln-Lys-Asn-Val 141 Structure289Gln-Lys-Arg-Pro-Ser-Gln-Arg-Ser-Lys-Tyr-Leu 142 Structure290Gln-Lys-Arg-Pro-Ser-Gln-Arg-Ser-Lys-Tyr-Leu 142 Structure291Gln-Lys-Arg-Pro-Ser-Gln-Arg-Ser-Lys-Tyr-Leu 142 Structure292Gly-Lys-Gly-Arg-Gly-Leu-Ser-Leu-Ser-Arg-Phe-Ser-Trp-Gly- 143 AlaStructure293 Gly-Lys-Gly-Arg-Gly-Leu-Ser-Leu-Ser-Arg-Phe-Ser-Trp-Gly-143 Ala Structure294Gly-Lys-Gly-Ala-Gly-Leu-Ser-Leu-Ser-Arg-Phe-Ser-Trp-Gly- 144 AlaStructure295 Gly-Lys-Gly-Ala-Gly-Leu-Ser-Leu-Ser-Arg-Phe-Ser-Trp-Gly-144 Ala Structure296Gly-Lys-Gly-Arg-Gly-Leu-Ser-Leu-Ser-Ala-Phe-Ser-Trp-Gly- 144 AlaStructure297 Gly-Lys-Gly-Arg-Gly-Leu-Ser-Leu-Ser-Ala-Phe-Ser-Trp-Gly-144 Ala Structure298 Arg-Lys-Glu-Val-Tyr 145 Structure299Arg-Lys-Glu-Val-Tyr 145 Structure300 Arg-Lys-Glu-Val-Tyr 145Structure301 Arg-Lys-Glu-Val-Tyr 145 Structure302D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp 146 Structure303D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp 146 Structure304Asp-Ser-Phe-Val-Xaa21-Leu-Met 147 Structure305Asp-Lys-Phe-Val-Gly-N-Me-Leu-Nle 148 Structure306Asp-Lys-Phe-Val-Gly-N-Me-Leu-Nle 148 Structure307Asp-Ser-Phe-Val-Gly-Leu-Nle 149 Structure308Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys 150 Structure309Asp-Tyr-D-Trp-Val-D-Trp-D-Trp-Lys 150 Structure310Asp-Met-His-Asp-Phe-Phe-Val-Gly-Leu-Met 151 Structure311Leu-Asp-Gln-Trp-Phe-Gly 152 Structure312Asp-Met-His-Asp-Phe-Phe-N-Me-Phe-Gly-Leu-Met 153 Structure313Asp-Met-His-Asp-Phe-Phe-Pro-Gly-Leu-Met 154 Structure314Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met 155 Structure315D-Arg-D-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Leu 156 Structure316D-Arg-D-Pro-Lys-Pro-Gln-Gln-D-Trp-Phe-D-Trp-Leu-Leu 156 Structure317Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-D-Pro-Pro-Trp 157 Structure318Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-D-Pro-Pro-Trp 157 Structure319Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-D-Pro-MeLeu-Trp 158 Structure320Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-D-Pro-MeLeu-Trp 158 Structure321Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Pro-Leu-Met 159 Structure322Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Pro-Leu-Met 159 Structure323Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Sar-Leu-Xaa22 160 Structure324Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Sar-Leu-Xaa22 160 Structure325Tyr-D-Phe-Phe-D-His-Leu-Met 161 Structure326Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle 162 Structure327Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle 162 Structure328Arg-Ala-D-Trp-Phe-D-Pro-Pro-Nle 162 Structure328Ala-Ala-D-Trp-Phe-D-Pro-Pro-Nle 163 Structure330Tyr-Phe-Leu-Leu-Arg-Asn-Pro 164 Structure331Met-Ser-Arg-Pro-Ala-Cys-Pro-Asn-Asp-Lys-Tyr-Glu 165 Structure332Met-Ser-Arg-Pro-Ala-Cys-Pro-Asn-Asp-Lys-Tyr-Glu 165 Structure333Val-Val-Xaa23-Ala-Xaa23 166 Structure334 Val-Val-Xaa23-Ala-Xaa23 166Structure335 Val-Val-Xaa23-Ala-Xaa23 166 Structure336His-Cys-Lys-Phe-Trp-Trp 167 Structure337 His-Cys-Lys-Phe-Trp-Trp 167Structure338 Thr-Tyr-Ile-Cys-Glu-Val-Glu-Asp-Gln-Lys-Glu-Glu 168Structure339 Thr-Tyr-Ile-Cys-Glu-Val-Glu-Asp-Gln-Lys-Glu-Glu 168Structure340 Tyr-Ala-Gly-Ala-Val-Val-Asn-Asp-Leu 169 Structure341Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg 170 Structure342Ile-Leu-Pro-Trp-Lys-Trp-Pro-Trp-Trp-Pro-Trp-Arg-Arg 170 Structure343Thr-Asp-Val-Asn 171

The structures of the unusual amino acids (Xaa1, Xaa2, Xaa3, Xaa4, Xaa5,Xaa7, Xaa9, Xaa13, Xaa14, Xaa15, Xaa17, Xaa19, Xaa21, Xaa22, Xaa23,Xaa24, Xaa25, and Xaa26) appeared in SEQ ID NO. 1-172 are listed inTable B:

TABLE B Unusual amino acids appeared in SEQ ID NO. 1-172 AbbreviationStructure Xaa

  wherein R₄ is defined the same as supra. Xaa1 (MePhe)

Xaa2 (Met(O2)-L)

Xaa3 (Retro- inverso-Thr)

Xaa4 (D-Pen)

Xaa5

Xaa7 (4-amino Phe)

Xaa9

Xaa13 (Ac-Dip)

Xaa14 (Cys(Acm))

Xaa15 (pGlf)

Xaa17 (D-NaI(2))

Xaa19

Xaa21

Xaa22

Xaa23

Xaa24

Xaa25

Xaa26

In certain embodiments, a peptide HPP/HPC includes a compound having astructure selected from the group consisting of Structures 2-345 asdefined supra, including stereoisomers and pharmaceutically acceptablesalts thereof, wherein:

HA, Ar, X, X₄, X₅, X₆, X₇, X₈, X₉, X₁₀, X₂₁, X₂₂, X₂₃, X₂₄, X₂₅, X₂₆,and X₂₇ are defined the same as supra;

R is selected from the group consisting of H, substituted andunsubstituted 1-20 carbon alkyl, substituted and unsubstitutedcycloalkyl, and substituted and unsubstituted heterocycloalkyl,substituted and unsubstituted 1-20 carbon alkoxyl, substituted andunsubstituted 1-20 carbon alkylthio, substituted and unsubstituted 1-20carbon alkylamino, substituted and unsubstituted aryl, and substitutedand unsubstituted heteroaryl residues;

R₁, R₂, R₄, R₅, R₆, R₇, R₈, R₉, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, andR₂₇ are independently selected from the group consisting of H, O,substituted and unsubstituted 1-20 carbon alkyl, substituted andunsubstituted cycloalkyl, and substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted 1-20 carbon alkoxyl,substituted and unsubstituted 1-20 carbon alkylthio, substituted andunsubstituted 1-20 carbon alkylamino, substituted and unsubstituted 1-20carbon alkenyl, substituted and unsubstituted 1-20 carbon alkynyl,substituted and unsubstituted aryl, and substituted and unsubstitutedheteroaryl residues;

In certain embodiments, a peptide HPP/HPC comprises a structure selectedform the group consisting of Structure 1a, Structure 1 b, Structure 1 c,Structure 1d, Structure 1e, Structure 1f, Structure 1g, and Structure1h:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

X₄, X₅, X₆, X₇, X₈, X₉, R₄, R₅, R₆, R₇, R₈, R₉, and HA are defined thesame as supra.

Solid-Phase Synthesis of Peptide HPP/HPC

Shorter peptides (<10 amino acids) can be synthesized by solution phasesynthesis, but it is very difficult for the synthesis of long peptidesby solution phase. HPPs/HPCs of peptides in the present disclosure aremodified peptides and cannot be synthesized by standard solid-phasepeptide synthesis method (from C-terminal to N-terminal).

In certain embodiments, a peptide HPP/HPC is synthesized from N-terminalto C-terminal, wherein the synthesis method comprises the followingsteps:

A method of preparing a peptide HPC using solid-phase synthesiscomprising:

-   -   a) providing a chemically modified resin (e.g. trityl chloride        resin and carbonate ester resin);    -   b) protecting the carboxylic group of all the natural or        modified amino acid residues as desired according to the peptide        HPC with a protecting group (e.g. 2-(4-nitrophenylsulfonyl)ethyl        group and 9-fluorenylmethyl group) to provide a COOH-protected        amino acid residue;    -   c) coupling the COOH -protected amino acid residue at the        N-terminal of the peptide HPC to the chemically modified resin        to provide an immobilized COOH-protected peptide HPC precursor        having one amino acid residue;    -   d) deprotecting the protected carboxylic group of the        immobilized COOH-protected peptide HPC precursor using        deprotecting reagents (e.g. 1% DBU/20% piperidine/79% DMF, or        other reagents that can deprotect the protected carboxylic        group); to provide an immobilized COOH -unprotected peptide HPC        precursor having one amino acid residue;    -   e) repeating steps c) and d) using the COOH-protected amino acid        residue of the peptide HPC until an immobilized C-unprotected        peptide HPC precursor having all amino acid residues except for        the C-terminal amino acid residue is provided;    -   f) linking a C-terminal amino acid residue with linking a        C-terminal amino acid residue with R_(T) via covalent bond to        provide a modified C-terminal amino acid wherein R_(T) is        selected from the group consisting of substituted and        unsubstituted alkyl, substituted and unsubstituted cycloalkyl,        substituted and unsubstituted heterocycloalkyl, substituted and        unsubstituted alkyloxyl, substituted and unsubstituted alkenyl,        substituted and unsubstituted alkynyl, substituted and        unsubstituted aryl, substituted and unsubstituted heteroaryl,        and transportational unit selected from the group consisting of        Structure Na, Structure Nb, Structure Nc, Structure Nd,        Structure Ne, Structure Nf, Structure Ng, Structure Nh,        Structure Ni, Structure Nj, Structure Nk, Structure Nl,        Structure Nm, Structure Nn, Structure No, Structure Np,        Structure Nq and Structure Nr as defined supra;    -   g) coupling the modified C-terminal amino acid to the        immobilized C-unprotected peptide HPC precursor obtained from        step e) to provide an immobilized peptide HPC; and    -   h) releasing the immobilized peptide HPC from the resin to        provide the peptide HPC.

In certain embodiments, a chemically modified resin can be coupleddirectly with the protected amino acid, or a chemically modified resincan be further modified first and then couple with the COOH-protectedamino acid;

In certain embodiments, a peptide HPP/HPC comprising a transportationalunit on the C-terminal amino acid is prepared by coupling to the peptidechain the C-terminal amino acid wherein the carboxylic group is linkedto a transportational unit as described supra. For example, thetransportational unit is selected from the group consisting of StructureNa, Structure Nb, Structure Nc, Structure Nd, Structure Ne, StructureNf, Structure Ng, Structure Nh, Structure Ni, Structure Nj, StructureNk, Structure Nl, Structure Nm, Structure Nn, Structure No, StructureNp, Structure Nq and Structure Nr as defined supra.

In certain embodiments, a peptide HP/HPC comprising a transportationalunit on the C-terminal amino acid is prepared by coupling to the peptidechain the C-terminal amino acid wherein the carboxylic group isprotected, deprotecting the carboxylic group, and finally coupling to atransportational unit. For example, the transportational unit isselected from the group consisting of Structure Na, Structure Nb,Structure Nc, Structure Nd, Structure Ne, Structure Nf, Structure Ng,Structure Nh, Structure Ni, Structure Nj, Structure Nk, Structure Nl,Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nq andStructure Nr as defined supra.

In certain embodiments, releasing the peptide HPP/HPC is accomplishedwith high yield. For example, in certain embodiments, the resin is atrityl chloride resin wherein the releasing step can be accomplished byreacting with TFA/DCM (e.g. 5%). In certain embodiments, the resin is acarbonate ester resin, and the releasing step can be accomplished byreacting with Pd—C (e.g. 10% in methanol) and H₂.

In certain embodiments, the coupling reaction is carried out in thepresence of coupling reagents. Examples of coupling reagents include,without limitation, HBTU/DIPEA/HOBt, TBTU/DIPEA/HOBt, BOP/DIPEA/HOBt,HATU/DIPEA/HOBt, and DIC/HOB, and combinations thereof.

As used herein, unless defined otherwise:

“DBU” means 1,8-diazabicyclo[5,4,0]undec-7-ene;“DMF” means dimethylformamide;“DIPEA” means N,N-diisopropylethylamine;“HBTU” means O-Benzotriazole-N,N,N,N′-tetramethyl-uronium-hexafluorophosphate;“HOBt” means 1-hydroxylbenzotriazole;“TBTU” meansO-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-tetrafluoroborate;“BOP” means benzotriazole-1-yl-N-oxy-tris(pyrrolidino)phosphoniumhexafluorophosphate;“HATU” meansN-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridino-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide;“DIC” means diisopropylcarbodiimide; and “TFA” means trifluoroaceticacid.

II. Pharmaceutical compositions comprising HPPs/HPCs

Another aspect of the invention relates to a pharmaceutical compositioncomprising at least one peptide HPP/HPC and a pharmaceuticallyacceptable carrier.

The term “pharmaceutically acceptable carrier” as used herein means apharmaceutically-acceptable material, composition or vehicle, such as aliquid or solid filler, diluent, excipient, solvent or encapsulatingmaterial, involved in carrying or transporting a HPP/HPC from onelocation, body fluid, tissue, organ (interior or exterior), or portionof the body, to another location, body fluid, tissue, organ, or portionof the body.

Each carrier is “pharmaceutically acceptable” in the sense of beingcompatible with the other ingredients, e.g., a HPP/HPC, of theformulation and suitable for use in contact with the tissue or organ ofa biological system without excessive toxicity, irritation, allergicresponse, immunogenicity, or other problems or complications,commensurate with a reasonable benefit/risk ratio.

Some examples of materials which can serve aspharmaceutically-acceptable carriers include: (1) sugars, such aslactose, glucose and sucrose; (2) starches, such as corn starch andpotato starch; (3) cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4)powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients,such as cocoa butter and suppository waxes; (9) oils, such as peanutoil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil andsoybean oil; (10) glycols, such as propylene glycol; (11) polyols, suchas glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters,such as ethyl oleate and ethyl laurate; (13) agar; (14) bufferingagents, such as magnesium hydroxide and aluminum hydroxide; (15) alginicacid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer'ssolution; (19) alcohol, such as ethyl alcohol and propane alcohol; (20)phosphate buffer solutions; and (21) other non-toxic compatiblesubstances employed in pharmaceutical formulations such as acetone.

The pharmaceutical compositions may contain pharmaceutically acceptableauxiliary substances as required to approximate physiological conditionssuch as pH adjusting and buffering agents, toxicity adjusting agents andthe like, for example, sodium acetate, sodium chloride, potassiumchloride, calcium chloride, sodium lactate and the like.

In one embodiment, the pharmaceutically acceptable carrier is an aqueouscarrier, e.g. buffered saline and the like. In certain embodiments, thepharmaceutically acceptable carrier is a polar solvent, e.g. water,acetone and alcohol.

The concentration of HPP/HPC in these formulations can vary widely, andwill be selected primarily based on fluid volumes, viscosities, bodyweight and the like in accordance with the particular mode ofadministration selected and the biological system's needs. For example,the concentration can be 0.0001% to 100%, 0.001% to 50%, 0.01% to 30%,0.1% to 10% wt.

The compositions of the invention can be administered for prophylactic,therapeutic, and/or hygienic use. Such administration can be topical,mucosal, e.g., oral, nasal, vaginal, rectal, parenteral, transdermal,subcutaneous, intramuscular, intravenous, via inhalation, ophthalmic andother convenient routes. The pharmaceutical compositions can beadministered in a variety of unit dosage forms depending upon the methodof administration. For example, unit dosage forms suitable for oraladministration include powder, tablets, pills, capsules and lozenges.

Thus, a typical pharmaceutical composition for intravenousadministration would be about 10⁻¹⁰ g to about 100 g, about 10⁻¹⁰ g toabout 10⁻³ g, about 10⁻⁹ g to about 10⁻⁶ g, about 10⁻⁶ g to about 100 g,about 0.001 g to about 100 g, about 0.01 g to about 10 g, or about 0.01g to about 1 g per subject per day. Dosages from about 0.01 mg, up toabout 50 g, per subject per day may be used. Actual methods forpreparing parenterally administrable compositions will be known orapparent to those skilled in the art and are described in more detail insuch publications as Remington's Pharmaceutical Science, 15th ed., MackPublishing Company, Easton, Pa. (1980).

III. Applications of HPPs/HPCs

i) Methods for Penetrating a Biological Barrier.

Another aspect of the invention relates to a method of using acomposition of the invention in penetrating one or more biologicalbarriers in a biological subject. The method comprises a step ofadministering to a biological subject a HPP/HPC or a peptide orpeptide-related compound, or a pharmaceutical composition thereof. Incertain embodiments, a HPP/HPC exhibits more than about 10 times orhigher, 50 times or higher, >about 100 times or higher, >about 200 timehigher, >about 300 times or higher, >about 500 times or higher, >about1,000 times or higher penetration rate through one or more biologicalbarriers than its parent drug.

The term “biological barrier” as used herein refers to a biologicallayer that separates an environment into different spatial areas orcompartments, which separation is capable of modulating (e.g.restricting, limiting, enhancing or taking no action in) the passingthrough, penetrating or translocation of substance or matter from onecompartment/area to another. The different spatial areas or compartmentsas referred to herein may have the same or different chemical orbiological environment(s). The biological layer as referred hereinincludes, but is not limited to, a biological membrane, a cell layer, abiological structure, an inner surface of subjects, organisms, organs orbody cavities, an external surface of subjects, organisms, organs orbody cavities, or any combination or plurality thereof.

Examples of a biological membrane include a lipid bilayer structure,eukaryotic cell membrane, prokaryotic cell membrane, and intracellularmembrane (e.g., nucleus or organelle membrane, such as membrane orenvelope of Golgi apparatus, rough and smooth endoplasmic reticulum(ER), ribosomes, vacuoles, vesicles, liposomes, mitochondria, lysosome,nucleus, chloroplasts, plastids, peroxisomes or microbodies).

The lipid bilayer referred to herein is a double layer of lipid-classmolecules, including, but not limited to, phospholipids and cholesterol.In a particular embodiment, lipids for bilayer are amphiphilic moleculesconsisting of polar head groups and non-polar fatty acid tails. Thebilayer is composed of two layers of lipids arranged so that theirhydrocarbon tails face one another to form an oily core held together bythe hydrophobic effect, while their charged heads face the aqueoussolutions on either side of the membrane. In another particularembodiment, the lipid bilayer may contain one or more embedded proteinand/or sugar molecule(s).

Examples of a cell layer include a lining of eukaryotic cells (e.g.,epithelium, lamina propria and smooth muscle or muscularis mucosa (ingastrointestinal tract)), a lining of prokaryotic cells (e.g., surfacelayer or S-layer which refers to a two dimensional structuremonomolecular layer composed of identical proteins or glycoproteins,specifically, an S-layer refers to a part of a cell envelope commonlyfound in bacteria and archaea), a biofilm (a structured community ofmicroorganisms encapsulated within a self-developed polymeric matrix andadherent to a living or inert surface), and a plant cell layer (e.g.,empidermis). The cells may be normal cells or pathological cells (e.g.disease cells, cancer cells).

Examples of biological structures include structures sealed by tight oroccluding junctions which provide a barrier to the entry of toxins,bacteria and viruses, e.g. the blood milk barrier and the blood brainbarrier (BBB). In particular, BBB is composed of an impermeable class ofendothelium, which presents both a physical barrier through tightjunctions adjoining neighboring endothelial cells and a transportbarrier comprised of efflux transporters. The biological structure mayalso include a mixture of cells, proteins and sugars (e.g. blood clots).

Examples of the inner surface of subjects, organisms, organs or bodycavities include buccal mucosa, esophageal mucosa, gastric mucosa,intestinal mucosa, olfactory mucosa, oral mucosa, bronchial mucosa,uterine mucosa and endometrium (the mucosa of the uterus, inner layer ofthe wall of a pollen grain or the inner wall layer of a spore), or acombination or plurality thereof.

Examples of the external surface of subjects, organisms, organs or bodycavities include capillaries (e.g. capillaries in the heart tissue),mucous membranes that are continuous with skin (e.g. such as at thenostrils, the lips, the ears, the genital area, and the anus), outersurface of an organ (e.g. liver, lung, stomach, brain, kidney, heart,ear, eye, nose, mouth, tongue, colon, pancreas, gallbladder, duodenum,rectum stomach, colonrectum, intestine, vein, respiratory system,vascular, the anorectum and pruritus ani), skin, cuticle (e.g. deadlayers of epidermal cells or keratinocytes or superficial layer ofoverlapping cells covering the hair shaft of an animal, a multi-layeredstructure outside the epidermis of many invertebrates, plant cuticles orpolymers cutin and/or cutan), external layer of the wall of a pollengrain or the external wall layer of a spore), and a combination orplurality thereof.

In addition, a biological barrier further includes a sugar layer, aprotein layer or any other biological layer, or a combination orplurality thereof. For example, skin is a biological barrier that has aplurality of biological layers. A skin comprises an epidermis layer(outer surface), a demis layer and a subcutaneous layer. The epidermislayer contains several layers including a basal cell layer, a spinouscell layer, a granular cell layer, and a stratum corneum. The cells inthe epidermis are called keratinocytes. The stratum corneum (“hornylayer”) is the outmost layer of the epidermis, wherein cells here areflat and scale-like (“squamous”) in shape. These cells contain a lot ofkeratin and are arranged in overlapping layers that impart a tough andoilproof and waterproof character to the skin's surface.

iI) Methods for Diagnosing a Condition in a Biological System.

Another aspect of the invention relates to a method of using acomposition of the invention in diagnosing a condition in a biologicalsystem. The method comprises the following steps:

1) administrating a composition comprising a peptide HPP/HPC to thebiological subject;

2) detecting the presence, location or amount of the HPP/HPC, thefunctional unit of the HP P/HPC or a metabolite thereof in thebiological subject; and

3) determining a condition in the biological system.

In certain embodiments, the HPP/HPC (or the agent cleaved from theHPP/HPC) aggregates in the site of action where a condition occurs. Incertain embodiments, the presence, location or amount of the functionalunit of the HPP/HPC is also detected. In certain embodiments, the onset,development, progress, or remission of a condition (e.g., cancer)associated is also determined.

In certain embodiments, the HPP/HPC is labeled with or conjugated to adetectable agent. Alternatively, the HPP/HPC is prepared to includeradioisotopes for detection. Numerous detectable agents are availablewhich can be generally grouped into the following categories:

(a) Radioisotopes, such as ³⁵S, ¹⁴C, ¹³C_(,) ¹⁵N, ¹²⁵I, ³H, and ¹³¹I.The diagnostic agent can be labeled with the radioisotope using thetechniques known in the art and radioactivity can be measured usingscintillation counting; in addition, the diagnostic agent can be spinlabeled for electron paramagnetic resonance for carbon and nitrogenlabeling.

(b) Fluorescent agents such as BODIPY, BODIPY analogs, rare earthchelates (europium chelates), fluorescein and its derivatives, FITC, 5,6carboxyfluorescein, rhodamine and its derivatives, dansyl, Lissamine,phycoerythrin, green fluorescent protein, yellow fluorescent protein,red fluorescent protein and Texas Red. Fluorescence can be quantifiedusing a fluorometer.

(c) Various enzyme-substrate agents, such luciferases (e.g., fireflyluciferase and bacterial luciferase), luciferin,2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidasesuch as horseradish peroxidase (HRPO), alkaline phosphatase,β-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g.,glucose oxidase, galactose oxidase, and glucose-6-phosphatedehydrogenase), heterocyclic oxidases (such as uricase and xanthineoxidase), lactoperoxidase, microperoxidase, and the like. Examples ofenzyme-substrate combinations include, for example: (i) Horseradishperoxidase (HRPO) with hydrogen peroxidase as a substrate, wherein thehydrogen peroxidase oxidizes a dye precursor (e.g., orthophenylenediamine (OPD) or 3,3′,5,5′-tetramethyl benzidine hydrochloride (TMB));(ii) alkaline phosphatase (AP) with para-Nitrophenyl phosphate aschromogenic substrate; and (iii) β-D-galactosidase (β-D-Gal) with achromogenic substrate (e.g., p-nitrophenyl-β-D-galactosidase) orfluorogenic substrate 4-methylumbelliferyl-β-D-galactosidase.

In certain embodiments, the detectable agent is not necessarilyconjugated to the diagnostic agent but is capable of recognizing thepresence of the diagnostic agent and the diagnostic agent can bedetected.

In certain embodiments, a peptide HPP/HPC can be provided in a kit,i.e., a packaged combination of reagents in predetermined amounts withinstructions for performing the diagnostic assay. Where the HPP/HPC islabeled with an enzyme, the kit will include substrates and cofactorsrequired by the enzyme (e.g., a substrate precursor which provides thedetectable chromophore or fluorophore). In addition, other additives maybe included such as stabilizers, buffers (e.g., a block buffer or lysisbuffer) and the like. The relative amounts of the various reagents maybe varied widely to provide for concentrations in solution of thereagents which substantially optimize the sensitivity of the assay.Particularly, the reagents may be provided as dry powders, usuallylyophilized, including excipients which on dissolution will provide areagent solution having the appropriate concentration.

iii) Methods for Screening a Substance for a Desired Character

Another aspect of the invention relates to a method of screening aHPP/HPC for a desired character.

In certain embodiments, the method comprises:

1) covalently linking a test functional unit to a transportational unitthrough a linker to form a test composition (or covalently linking afunctional unit to a test transportational unit through a linker, orcovalently linking a functional unit to a transportational unit througha test linker)2) administrating the test composition to a biological system; and3) determining whether the test composition has the desired nature orcharacter.

In one embodiment, a desired character may include, for example, 1) theability of a test functional unit to form a high penetration compositionor convert back to a parent drug, 2) the penetration ability and/or rateof a test composition, 3) the efficiency and/or efficacy of a testcomposition, 4) the transportational ability of a test transportationalunit, and 5) the cleavability of a test linker.

iv) Methods for Treating a Condition in a Biological Subject

Another aspect of the invention relates to a method of using acomposition of the invention in treating a condition in a biologicalsystem. The method comprises administrating the pharmaceuticalcomposition to the biological system.

The term “treating” as used herein means curing, alleviating,inhibiting, or preventing. The term “treat” as used herein means cure,alleviate, inhibit, or prevent. The term “treatment” as used hereinmeans cure, alleviation, inhibition or prevention.

The term “biological system,” “biological subject” or “subject” as usedherein means an organ, a group of organs that work together to perform acertain task, an organism, or a group of organisms. The term “organism”as used herein means an assembly of molecules that function as a more orless stable whole and has the properties of life, such as animal, plant,fungus, or micro-organism.

The term “animal” as used herein means an eukaryotic organismcharacterized by voluntary movement. Examples of animal include, withoutlimitation, vertebrata (e.g. human, mammals, birds, reptiles,amphibians, fishes, marsipobranchiata and leptocardia), tunicata (e.g.thaliacea, appendicularia, sorberacea and ascidioidea), articulata (e.g.insecta, myriapoda, malacapoda, arachnida, pycnogonida, merostomata,crustacea and annelida), gehyrea (anarthropoda), and helminthes (e.g.rotifera).

The term “plant” as used herein means organisms belonging to the kingdomPlantae. Examples of plant include, without limitation, seed plants,bryophytes, ferns and fern allies. Examples of seed plants include,without limitation, cycads, ginkgo, conifers, gnetophytes, angiosperms.Examples of bryophytes include, without limitation, liverworts,hornworts and mosses. Examples of ferns include, without limitation,ophioglossales (e.g. adders-tongues, moonworts, and grape-ferns),marattiaceae and leptosporangiate ferns. Examples of fern alliesinclude, without limitation, lycopsida (e.g. clubmosses, spikemosses andquillworts), psilotaceae (e.g. lycopodiophyta and whisk ferns) andequisetaceae (e.g. horsetails).

The term “fungus” as used herein means a eukaryotic organism that is amember of the kingdom Fungi. Examples of fungus include, withoutlimitation, chytrids, blastocladiomycota, neocallimastigomycota,zygomycota, glomeromycota, ascomycota and basidiomycota.

The term “micro-organism” as used herein means an organism that ismicroscopic (e.g. with length scale of micrometer). Examples ofmicro-organism include, without limitation, bacteria, fungi, archaea,protists and microscopic plants (e.g. green algae) and microscopicanimals (e.g. plankton, planarian and amoeba).

Some examples of the conditions the method can treat include conditionsthat can be treated by the parent drug of the HPP/HPC.

v). Methods of Using Peptide HPPs/HPCs and Pharmaceutical CompositionsThereof in Treatments.

Another aspect of the invention relates to a method of using peptideHPPs/HPCs, or pharmaceutical compositions thereof in treating acondition in a biological system or subject by administrating a peptideHPP/HPC, or a pharmaceutical composition thereof to the biologicalsystem or subject.

Peptides and peptides-related compounds can be used to regulate a widerange of biological processes in a biological system. Conditions thatare related to such biological processes are treatable by thecorresponding peptides or peptide-related compounds, and thereforetreatable by peptide HPPs/HPCs, and a pharmaceutical compositionthereof.

Such conditions include, but are not limited to, aging, angina,antithrombin deficiency, arrhythmia, atheroscierosis, artrialfibrillation, atrial flutter, blood clots, cardiacischemia, cardiacsurgery, cardiomyopathy, cardiovascular abnormalities, carotid arterydisease, chest pain, circulation disorders, claudication, collagenvascular diseases, congenital heart diseases, congestive heart failure,coronary artery disease, diabetes, diabetes and hypertension,dyslipidemia, dysrhythmia, elevated triglycerides, heart defect, heartdisease, heart failure, heart valve disease, hemangioma, highchlolesterol, hypertriglyceridemia, intermittent claudication,hypertension, Kawasaki disease, heart attack, myocardial ischemia,orthostatic hypotension, peripheral arterial disease, peripheralarterial occlusive disease, peripheral vascular disease, Raynaud'sdisease, smoking cessation, tachycardia (fast heart rate), thrombosis,varicose veins, vascular diseases, venous leg ulcers, gingivitis, gumdiseases, halitosis, oral cancer, periodontal disease, temporomandibulardisorders, temporomandibular joint syndrome, sunburn, acne, skin aging,alopecia, anesthesia, athlete's foot, atopic dermatitis, bed sores(decubitus ulcers), bunions, burns, burn infections, cold sores (herpeslabialis infections), congenital skin diseases, contact dermatitis,cutaneous lupus erythematosus, diabetic foot ulcers, eczema, excessivesweating, fabry disease, fungal infections, genital herpes, genitalwarts, hair loss, hair removal, hand dermatitis, head lice, hemangioma,hereditary angioedema, herpes simplex infections, herpes Zosterinfections, herpetic neuralgia, hives, ichthyosis, ischemic foot ulcers,keratoses, lupus, male pattern baldness, malignant melanoma, medicalprosthetics, melanoma, molluscum contagiosum, mycosis fungoides,onychomycosis, pemphigus vulgaris, postherpetic neuralgia, pressureulcers, psoriasis and psoriatic disorders, psoriatic arthritis, razorbumps, rosacea, sarcoidosis, scalp disorders, scar tissue, scleroderma,seborrhea, seborrheic dermatitis, shingles, skin cancer, skininfections, skin lipomas, skin wounds, solar lentigines, sporotrichosis,staphylococcai skin infections, stasis dermatitis, stretch marks,systemic fungai infections, sun poisoning, ringworm, tinea capitis,tinea versicolor, urticaria, vitiligo, warts, wounds, acromegaly,adrenal cancer, congenital adrenal hyperplasia, diabetes mellitus (typeI and type II), diabetes mellitus (type I), diabetes mellitus (type II),diabetic gastroparesis, diabetic kidney disease, diabetic macular edema,diabetic neuropathy, diabetic retinopathy, diabetic vitreous hemorrhage,dyslipidemia, female hormonal deficiencies/abnormalities, Fredricksontype III. hyperlipoproteinemia, growth hormonedeficiencies/abnormalities, gynecomastia, hair removal, hyperlipidemia,hormone deficiencies, hot flash, hyperparathyroidism, idiopathic shortstature, indication: diabetes type II, male hormonaldeficiencies/abnormalities, McCune-Albright syndrome, menopausedisorders, metabolic syndrome, obesity, ovarian cancer, pancreaticcancer, pancreatic disorders, pancreatitis, parathyroid cancer,parathyroid disease, parathyroid disorders, perimenopause, pituitarydisorders, polycystic ovarian syndrome, post menopause disorders, postmenopause osteopenia, precocious puberty, primary insulinhypersecretion, severe short stature, sexual dysfunction, thyroiddisease, thyroid disorders, Turner syndrome, Wilms' tumor, Wilson'sdisease, abdominal cancer, achalasia, alpha 1 antitrypsin deficiency,anal fissures, appendicitis, Barrett's esophagus, biliary tract cancer,bowel dysfunction, celiac disease, chronic diarrhea, clostridiumdifficile-associated diarrhea, colon cancer, colon polyps, colorectalcancer, constipation, Crohn's disease, diabetic gastroparesis, digestivesystem neoplasms, duodenal ulcers, Fabry disease, fecal incontinence,functional dyspepsia, gall bladder disorders, gastric cancer, gastriculcers, gastroenteritis, gastroesophageal reflux disease,gastrointestinal disease and disorders, gastroparesis, heartburn,helicobacter pylori, hemorrhoids, hepatic encephalopathy, hepatitis,ileus, infectious colitis, inflammatory bowel disease, intra-abdominalinfections, irritable bowel syndrome, liver disease, liver disorders,non-erosive reflux disease, non-ulcer dyspepsia, organ rejectionfollowing organ transplantation, post-operative nausea and vomiting,vomiting, rectal cancer, rectal disorders, recurrent diarrhea, stomachcancer, stomach discomfort, ulcerative colitis, abnormal blood vessels,acute myelogenous leukemia, anemia, anemia (non-Hodgking lymphoma),non-small-cell lung cancer, anemic cancer, aneurysm, antiphospholipidsyndrome, antithrombin deficiency, aplastic anemia, blood clots,candidemia/candidiasis, chronic renal anemia, Gaucher disease,hematologic cancer, hematological disorders, paroxysmal hemoglobinuria,hemorrhages, hypercalcemia, hypogammaglobulinemia, hyponatremia,idiopathic thrombocytopenic purpura, islet cell cancer, leukemia, B-celllymphoma, lymphomas, multiple myelomas, myelodysplastic syndromes,myocardial ischemia, occlusions, platelet deficiencies, plateletdisorders, red cell disorders, renal anemia, sezary syndrome, sicklecell disease, T-cell lymphoma, thalassemia, thrombocytopenia, vonWillebrand's disease, white cell disorders, acquired immune deficiencysyndrome (AIDS), AIDS related infections, acute rhinitis, allergies,asthma, anal dysplasia, bacterial infections, canker sores, celiacdisease, cervical dysplasia, chickenpox, chronic fatigue syndrome,common cold, common variable immunodeficiency, bacterial conjunctivitis,chronic obstructive pulmonary disease, cutaneous candidiasis, cutaneousT-cell lymphoma, cytomegalovirus infections, dermatomyositis, fever,graft-versus-host disease, hepatitis, hepatitis B, hepatitis C, HIVinfections, HIV/AIDS, human papilloma virus infections,hypogammaglobulinemia, idiopathic inflammatory myopathies, influenza,intra-abdominal infections, Kaposi's sarcoma, lupus, lyme tick disease,mycobacterium avium complex infection, meningitis, onychomycosis, oralcandidiasis, pneumonia, polymyositis (inflammatory muscle disease),postherpetic neuralgia, primary immunodeficiency disorders, respiratorysyncytial virus infection, rheumatic fever, allergic rhinitis, rotavirusinfection, sarcoidosis, sepsis and septicemia, sexually transmitteddiseases, shingles, Sjogren's syndrome, smallpox, soft tissueinfections, staphylococcal infections, staphylococcal skin infections,strep throat, systemic candidiasis, systemic lupus erythematosus, throatand tonsil infections, urticaria, vancomycin resistant enterococci, westnile virus infections, acromegaly, ankylosing spondylitis, bone loss,athletic injuries, bone diseases, bone metastases, breast pain, bunions,bursitis, carpal tunnel syndrome, cartilage injuries, chest pain,chronic back pain, chronic leg pain, chronic pain, chronic shoulderpain, claudication, congenital lactic acidosis, connective tissuediseases, dermatomyositis, dupurtren's disease, fibromyalgia, Frozenshoulder, adhesive capsulitis, gout (hyperuricemia), idiopathicinflammatory myopathies, intermittent claudication, joint injuries, kneeinjuries, multiple sclerosis, muscle pain, muscular dystrophy,musculoskeletal diseases, myasthenia gravis (chronic weakness),myasthenia gravis generalized, orthopedics, osteoarthritis,osteomyelitis, osteoporosis, osteosarcoma, Paget's disease, partialmedial meniscectomy, parathyroid disease, post-menopausal osteopenia,post-menopausal osteoporosis, reflex sympathetic dystrophy syndrome,rheumatoid arthritis, sciatica, spinal cord disorders, spinal cordmalignancy, spine athroplasty, sprains, tendon injuries, tennis elbow,tic disorders, anal dysplasia, benign prostatic hyperplasia, bladdercancer, bladder disorders, blood cancers, catheter complications,chronic pelvic pain, diabetic kidney disease, enuresis, erectiledysfunction, fabry disease, nocturia, genitourinary prolapse,glomerulonephritis, glomerulosclerosis, idiopathic membranousnephropathy, impotence, interstitial cystitis, kidney cancer, kidneydisease, kidney failure, kidney stones, liver cancer, low testosterone,mastectomy, medical prosthetics, nephropathy, Peyronie's disease,premature ejaculation, prostate cancer, prostate disorders, prostaticintraepithelial neoplasia, proteinuria, Reiter's syndrome, renal arterydisease, renal cell carcinoma, renal failure, testicular cancer,tyrosinemia, urethral strictures, urinary incontinence, urinary tractinfections, urothelial tract cancer, male erectile dysfunction andfemale sex dysfunction, systemic blood pressure, abortion, hypotensivecontrol, inhibition of platelet aggregation, pulmonary diseases,gastrointestinal disease, inflammation, shock, reproduction, fertility,obesity.

Conditions related to platelet aggregation include, for example,thromboembolis after surgery, carotid endarterectomy, the recurrence ofstenosis after coronary angioplasty, thromboembolis complications inchronic arterial fibrillation, aortocornonary-artery-bypass graftocclusion, heart attack, stroke, multi-infract dementia, dementia,hemodialysis shunt thrombosis and arterial embolic complications inpatients' prosthetic heart valves.

Some examples of the conditions that are treatable by a methodcomprising using a peptide HPP/HPC, or a pharmaceutical compositionthereof include, without limitation, peptide-hormone related conditions,inflammation and related conditions, platelet aggregation relatedconditions, neuropeptide related conditions, microorganism relatedconditions and other conditions regulated by peptides or peptide-relatedcompounds.

In certain embodiments, a method of treating a peptide treatablecondition comprises administering to a biological system a peptideHPP/HPC of a peptide or a peptide-related compound such asangiotentensin, angiotensin II antagonists, angiotentensin II AT2receptor, antimicrobial peptides, anti-oxytocin, hormones, antidiuretichormones, adrenocorticotropic hormones, antimicrobial peptide,anti-inflammatory peptide, bradykinin, bradykinin antagonist, endothelinpeptides, endothelin peptide antagonist, gastrin, calcitonin,melanoma-associated antigen peptide, laminin peptide, fibrinogenpeptide, EAE inducing peptides, growth factors, growth hormone releasingpeotides, somatostatin, hormone releasing hormones, luteinizing hormonereleasing hormone, neuropeptide, melanocyte stimulating hormones, sleepinducing peptide, amyloid peptide, tuftsin, retro inverso-tuftsin,enterostatins, Melanocortin II, and opioid peptides and mimics.

In certain embodiments, a method of treating a peptide-hormone relatedcondition comprises administering to a biological system a HPP/HPC of apeptide-hormone or a peptide-hormone related compound, or apharmaceutical composition thereof. In a biological system, hormonesregulate a wide range of processes such as energy levels, reproduction,growth and development, homeostasis, and reactions to surroundings,stress and injury. Examples of peptide-hormone related conditionsinclude, without limitation:

a) menopause;b) bone diseases, e.g. osteoporosis, Paget's disease and bonemetastases;c) growth hormone deficiency;d) hyperthyroidism or hypothyroidism;e) metabolism disorder, e.g. obesity, abnormal blood glucose level,abnormal blood lipid level, diabetes mellitus (type I or/and type II)and diabetes-induced complications, including diabetic retinopathy,necrobiotic ulcers, and diabetic proteinuria;f) abnormal blood pressure, e.g. hypertension and hypotension;g) skin condition, e.g. psoriasis and psoriatic disorders, acne, cysticacne, pus-filled or reddish bumps, comedones, papules, pustules,nodules, epidermoid cysts, keratosis pilaris, abnormal vascular skinlesions, birthmarks, moles (nevi), skin tags, scleroderma, vitiligo andrelated diseases, or aging spots (liver spots);h) autoimmune disease, e.g. discoid lupus erythematosus, systemic lupuserythematosus (SLE), autoimmune hepatitis, cleroderma, Sjogren'ssyndrome, rheumatoid arthritis, polymyositis, scleroderma, Hashimoto'sthyroiditis, juvenile diabetes mellitus, Addison disease, vitiligo,pernicious anemia, glomerulonephritis, pulmonary fibrosis, multiplesclerosis (MS) and Crohn's disease;i) eye disease, e.g. glaucoma, ocular hypertension, loss of vision afterophthalmic surgery, vision of a warm-blooded animal impaired by cystoidmacular edema and cataract;j) preeclamptic toxemia in high-risk women;k) male and female sexual dysfunction;j) allergy and asthma;k) insomnia;l) depression and related conditions;m) cardiovascular diseases, e.g. heart attack, unstable angina,peripheral occlusive arterial disease and stroke;n) tumor, e.g. benign tumor, breast cancer, colon-rectum cancer, oralcancer, lung or other respiratory system cancers, skin cancers, uteruscancer, pancreatic cancer, prostate cancer, genital cancer, urinaryorgans cancers, leukemia or other blood and lymph tissues cancer; ando) metastasis.

In certain embodiments, a method of treating a microorganism relatedcondition comprises administering to a biological system a HPP/HPC of ananti-microbial peptide or a anti-microbial peptide-related compound, ora pharmaceutical composition thereof. Examples of microorganisms relatedconditions include, without limitation, inflammation and relatedconditions:

a) pain;b) injuries;c) conditions related to microorganisms;d) inflammation related conditions, e.g. prostate gland inflammation(prostatitis), prostatocystitis, prostate enlarge fibrosis, hemorrhoids,Kawasaki syndrome, gastroenteritis, type-1 membranoproliferativeglomerulonephritis, Bartter's syndrome, chronic uveitis, ankylosingspondylitis, hemophilic arthropathy, inflamed hemorrhoids, postirradiation (factitial) proctitis, chronic ulcerative colitis,inflammatory bowel disease, cryptitis, periodontitis, arthritis, and aninflammatory condition in an organ selected from the group consisting ofliver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth,tongue, colon, pancreas, gallbladder, duodenum, rectum stomach,colonrectum, intestine, vein, respiratory system, vascular, theanorectum and pruritus ani.

In certain embodiments, a method of treating a neuropeptide-relatedcondition comprises administering to a biological system a HPP/HPC of aneuropeptide or a neuropeptide-related compound, or a pharmaceuticalcomposition thereof. Examples of neuropeptide related conditionsinclude, without limitation, pain, and neurodegenerative disease, e.g.Alzheimer's diseases and Parkinson's disease.

Other conditions that are treatable by a HPP/HPC or a pharmaceuticalcomposition thereof include, without limitation, conditions relate to:conditions related to platelet aggregation, e.g. thromboembolis aftersurgery, carotid endarterectomy, the recurrence of stenosis aftercoronary angioplasty, thromboembolis complications in chronic arterialfibrillation, aortocornonary-artery-bypass graft occlusion, heartattack, stroke, multi-infract dementia, dementia, hemodialysis shuntthrombosis and arterial embolic complications in patients' prostheticheart valves; antepartum, postpartum, anti-AD activities, antidiureticactivities, brain injury, calcium homeostasis, melanocye, activities ofCNS and phagocytosis,

In certain embodiments, a method of treating a condition in a subjectamelioratable or treatable with peptides or peptide-related compoundscomprises administering a therapeutic effective amount of a peptideHPP/HPC, or a pharmaceutical composition thereof to the subject.

A HPP/HPC or a pharmaceutical composition thereof can be administered toa biological system by any administration route known in the art,including without limitation, oral, enteral, buccal, nasal, topical,rectal, vaginal, aerosol, transmucosal, epidermal, transdermal, dermal,ophthalmic, pulmonary, subcutaneous, and/or parenteral administration.The pharmaceutical compositions can be administered in a variety of unitdosage forms depending upon the method of administration.

A parenteral administration refers to an administration route thattypically relates to injection which includes but is not limited tointravenous, intramuscular, intraarterial, intrathecal, intracapsular,intraorbital, intra cardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular,subarachnoid, intraspinal, and/or intrasternal injection and/orinfusion.

A HPP/HPC or a pharmaceutical composition thereof can be given to asubject in the form of formulations or preparations suitable for eachadministration route. The formulations useful in the methods of theinvention include one or more HPPs/HPCs, one or more pharmaceuticallyacceptable carriers therefor, and optionally other therapeuticingredients. The formulations may conveniently be presented in unitdosage form and may be prepared by any methods well known in the art ofpharmacy. The amount of active ingredient which can be combined with acarrier material to produce a single dosage form will vary dependingupon the subject being treated and the particular mode ofadministration. The amount of a HPP/HPC which can be combined with acarrier material to produce a pharmaceutically effective dose willgenerally be that amount of a HPP/HPC which produces a therapeuticeffect. Generally, out of one hundred percent, this amount will rangefrom about 1 percent to about ninety-nine percent of the HPP/HPC,preferably from about 20 percent to about 70 percent.

Methods of preparing these formulations or compositions include the stepof bringing into association a HPP/HPC with one or more pharmaceuticallyacceptable carriers and, optionally, one or more accessory ingredients.In general, the formulations are prepared by uniformly and intimatelybringing into association a HPP/HPC with liquid carriers, or finelydivided solid carriers, or both, and then, if necessary, shaping theproduct.

Formulations suitable for oral administration may be in the form ofcapsules, cachets, pills, tablets, lozenges (using a flavored basis,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a HPP/HPC as an active ingredient. A compoundmay also be administered as a bolus, electuary, or paste.

In solid dosage forms for oral administration (e.g., capsules, tablets,pills, dragees, powders, granules and the like), the HPP/HPC is mixedwith one or more pharmaceutically-acceptable carriers, such as sodiumcitrate or dicalcium phosphate, and/or any of the following: (1) fillersor extenders, such as starches, lactose, sucrose, glucose, mannitol,and/or silicic acid; (2) binders, such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone,sucrose and/or acacia; (3) humectants, such as glycerol; (4)disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and sodium carbonate,(5) solution retarding agents, such as paraffin, (6) absorptionaccelerators, such as quaternary ammonium compounds; (7) wetting agents,such as, for example, acetyl alcohol and glycerol monostearate; (8)absorbents, such as kaolin and bentonite clay; (9) lubricants, such atalc, calcium stearate, magnesium stearate, solid polyethylene glycols,sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.In the case of capsules, tablets and pills, the pharmaceuticalcompositions may also comprise buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules using such excipients as lactose or milk sugars, aswell as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered peptide orpeptidomimetic moistened with an inert liquid diluent. Tablets, andother solid dosage forms, such as dragees, capsules, pills and granules,may optionally be scored or prepared with coatings and shells, such asenteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of a HPP/HPC therein using, forexample, hydroxypropylmethyl cellulose in varying proportions to providethe desired release profile, other polymer matrices, liposomes and/ormicrospheres. They may be sterilized by, for example, filtration througha bacteria-retaining filter, or by incorporating sterilizing agents inthe form of sterile solid compositions which can be dissolved in sterilewater, or some other sterile injectable medium immediately before use.These compositions may also optionally contain pacifying agents and maybe of a composition that they release the HPP(s)/HPC(s) only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The HPP/HPCcan also be in micro-encapsulated form, if appropriate, with one or moreof the above-described excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the HPP/HPC, the liquid dosage forms may containinert diluents commonly used in the art, such as, for example, water orother solvents, solubilizing agents and emulsifiers, such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils(in particular, cottonseed, groundnut, corn, germ, olive, castor andsesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycolsand fatty acid esters of sorbitan, and mixtures thereof. Besides inertdiluents, the oral compositions can also include adjuvants such aswetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the HPP/HPC, may contain suspending agentsas, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations for rectal or vaginal administration may be presented as asuppository, which may be prepared by mixing one or more HPPs/HPCs withone or more suitable nonirritating excipients or carriers comprising,for example, cocoa butter, polyethylene glycol, a suppository wax or asalicylate, and which is solid at room temperature, but liquid at bodytemperature and, therefore, will melt in the rectum or vaginal cavityand release the active agent. Formulations which are suitable forvaginal administration also include pessaries, tampons, creams, gels,pastes, foams or spray formulations containing such carriers as areknown in the art to be appropriate.

Formulations for the topical or transdermal or epidermal or dermaladministration of a HPP composition include powders, sprays, ointments,pastes, creams, lotions, gels, solutions, patches and inhalants. Theactive component may be mixed under sterile conditions with apharmaceutically acceptable carrier, such as water, ethanol, and ethanolsolution, and with any preservatives, buffers, or propellants which maybe required. The ointments, pastes, creams and gels may contain, inaddition to the HPP composition, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof. Powders and sprays cancontain, in addition to the HPP composition, excipients such as lactose,talc, silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder, or mixtures of these substances. Sprays can additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

A HPP/HPC or a pharmaceutical composition thereof can be alternativelyadministered by aerosol. This can be accomplished by preparing anaqueous aerosol, liposomal preparation or solid particles containing theHPPs/HPCs. A nonaqueous (e.g., fluorocarbon propellant) suspension couldbe used. Sonic nebulizers can also be used. An aqueous aerosol is madeby formulating an aqueous solution or suspension of the agent togetherwith conventional pharmaceutically acceptable carriers and stabilizers.The carriers and stabilizers vary with the requirements of theparticular compound, but typically include nonionic surfactants (Tweens,Pluronics, or polyethylene glycol), innocuous proteins like serumalbumin, sorbitan esters, oleic acid, lecithin, amino acids such asglycine, buffers, salts, sugars or sugar alcohols. Aerosols generallyare prepared from isotonic solutions.

Transdermal patches can also be used to deliver HPP compositions to atumor site. Such formulations can be made by dissolving or dispersingthe agent in the proper medium. Absorption enhancers can also be used toincrease the flux of the peptidomimetic across the skin. The rate ofsuch flux can be controlled by either providing a rate controllingmembrane or dispersing the peptidomimetic in a polymer matrix or gel.

In certain embodiments, a transdermal therapeutic application systemcomprises a peptide HPP/HPC as an active substance for treatingconditions treatable by a parent compound thereof, wherein the system isa spray or rub-on solution further comprising a solvent that candissolve the peptide HPP/HPC. Examples of solvent include, withoutlimitation, organic solvents and inorganic solvents such as water,ethanol, isopropanol, acetone, DMSO, DMF, and combinations thereof.

In certain embodiments, a transdermal therapeutic application systemcomprises a peptide HPP/HPC as an active substance for treatingconditions treatable by a parent compound thereof, wherein the systemfurther comprises a subject comprising an active substance-containingmatrix layer and an impermeable backing layer. In certain embodiments,such subject is a patch or a bandage. In certain embodiments, suchsubject is an active substance reservoir comprising a permeable bottomfacing the skin, wherein by controlling the rate of release, the systemenables the active ingredient or a metabolite of the active ingredientto reach constantly optimal therapeutic blood levels to increaseeffectiveness and reduce the side effects of the active ingredient or ametabolite of the active ingredient.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Formulations suitable for parenteral administration comprise a HPP/HPCin combination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containantioxidants, buffers, bacterostats, solutes which render theformulation isotonic with the blood of the intended recipient orsuspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the formulations suitable for parenteral administrationinclude water, ethanol, polyols (e.g., such as glycerol, propyleneglycol, polyethylene glycol, and the like), and suitable mixturesthereof, vegetable oils, such as olive oil, and injectable organicesters, such as ethyl oleate. Proper fluidity can be maintained, forexample, by the use of coating materials, such as lecithin, by themaintenance of the required particle size in the case of dispersions,and by the use of surfactants.

Formulations suitable for parenteral administration may also containadjuvants such as preservatives, wetting agents, emulsifying agents anddispersing agents. Prevention of the action of microorganisms may beensured by the inclusion of various antibacterial and antifungal agents,for example, paraben, chlorobutanol, phenol sorbic acid, and the like.It may also be desirable to include isotonic agents, such as sugars,sodium chloride, and the like into the compositions. In addition,prolonged absorption of the injectable pharmaceutical form may bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

Injectable depot forms are made by forming microencapsule matrices of aHPP/HPC or in biodegradable polymers such as polylactide-polyglycolide.Depending on the ratio of the HPP/HPC to polymer, and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly (orthoesters) andpoly (anhydrides). Depot injectable formulations are also prepared byentrapping the HPP/HPC in liposomes or microemulsions which arecompatible with body tissue.

In certain embodiments, a peptide HPP/HPC, or a pharmaceuticalcomposition thereof is delivered to a disease or tumor site in atherapeutically effective dose. As is known in the art of pharmacology,the precise amount of the pharmaceutically effective dose of a HPP/HPCthat will yield the most effective results in terms of efficacy oftreatment in a given patient will depend upon, for example, theactivity, the particular nature, pharmacokinetics, pharmacodynamics, andbioavailability of a particular HPP/HPC, physiological condition of thesubject (including race, age, sex, weight, diet, disease type and stage,general physical condition, responsiveness to a given dosage and type ofmedication), the nature of pharmaceutically acceptable carriers in aformulation, the route and frequency of administration being used, andthe severity or propensity of a disease caused by pathogenic targetmicrobial organisms, to name a few. However, the above guidelines can beused as the basis for fine-tuning the treatment, e.g., determining theoptimum dose of administration, which will require no more than routineexperimentation consisting of monitoring the subject and adjusting thedosage. Remington: The Science and Practice of Pharmacy (Gennaro ed.20.sup.th edition, Williams & Wilkins PA, USA) (2000).

IV. Advantages

Peptides and related compounds are hydrophilic and have limited abilityto penetrate the skin membrane barrier. When peptides are taken orally,peptides and related compounds can be rapidly proteolysized byproteolytic enzymes in the GI tract in a few minutes. In the case ofinjection, administration of peptides is painful and in many casesrequires frequent and costly office visits to treat chronic conditions.

In certain embodiments, since a peptide HPP/HPC is capable of crossingone or more biological barriers with higher efficiency than its parentcompound, the HPP/HPC can be administered locally (e.g., topically ortransdermally) to reach a location where a condition occurs without thenecessity of a systematic administration (e.g., oral or parenteraladministration). A local administration and penetration of a HPP/HPCallows the HPP/HPC to reach the same level of local concentration of anagent or drug with much less amount or dosage of the HPP/HPC incomparison to a systematic administration of the parent agent or drug;alternatively, a higher level of local concentration which may not beafforded in the systematic administration, or if possible, requiressignificantly higher dosage of the agent in the systematicadministration. The high local concentration of the HPP/HPC or itsparent agent if being cleaved enables the treatment of a condition moreeffectively or much faster than a systematically delivered parent agentand the treatment of new conditions that may not be possible or observedbefore. The local administration of the HPP/HPC may allow a biologicalsubject to reduce potential sufferings from a systemic administration,e.g., adverse reactions associated with the systematic exposure to theagent, gastrointestinal/renal effects. Additionally, the localadministration may allow the HPP/HPC to cross a plurality of biologicalbarriers and reach systematically through, for example, generalcirculation and thus avoid the needs for systematic administration(e.g., injection) and obviate the pain associated with the parenteralinjection.

In certain embodiments, a HPP/HPC or a pharmaceutical compositionaccording to the invention can be administered systematically (e.g.,transdermally, orally or parenterally). The HPP/HPC or the active agent(e.g., drug or metabolite) of the HPP/HPC may enter the generalcirculation with a faster rate than the parent agent and gain fasteraccess to the action site a condition. Additionally, the HPP/HPC cancross a biological barrier (e.g., blood brain barrier) which has notbeen penetrated if a parent agent is administered alone and thus offernovel treatment of conditions that may not be possible or observedbefore.

For example, peptide HPPs/HPCs may demonstrate high penetration ratethrough a biological barrier (e.g., >about 10 times, >about 50times, >about 100 times, >about 200 times, >about 300 times, >about 1000times higher than if the peptides or peptide-related compounds areadministered alone). No or few adverse side effect is observed from thesubjects that took peptide HPPs/HPCs, while side effects (such asnausea, hair loss, and increased susceptibility to infection) areobserved from the subjects that took the parent peptides at the similardosage.

V. Examples

The following examples are provided to better illustrate the claimedinvention and are not to be interpreted in any way as limiting the scopeof the invention. All specific compositions, materials, and methodsdescribed below, in whole or in part, fall within the scope of theinvention. These specific compositions, materials, and methods are notintended to limit the invention, but merely to illustrate specificembodiments falling within the scope of the invention. One skilled inthe art may develop equivalent compositions, materials, and methodswithout the exercise of inventive capacity and without departing fromthe scope of the invention. It will be understood that many variationscan be made in the procedures herein described while still remainingwithin the bounds of the invention. It is the intention of the inventorsthat such variations are included within the scope of the invention.

Example 1 Preparation of a HPP/HPC from a Parent Drug

Preparation of a HPP/HPC from a Parent Drug which Contains at Least OneCarboxylic Group

In certain embodiments, a parent compound having the following Structure

-   -   is converted to a HPP/HPC having Structure L-1:

-   -   including stereoisomers and pharmaceutically acceptable salts        thereof, wherein:

F, L_(1C), L_(1N), L_(2C), L_(2N), L_(4C) and L_(4N) are defined assupra;

T_(C) is a transportational unit of a peptide HPP/HPC. For example,T_(C) is selected from the group consisting of Structure Na, StructureNb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, StructureNg, Structure Nh, Structure Ni, Structure Nj, Structure Nk, StructureNl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nqand Structure Nr as defined supra; and

T_(N) is selected from the group consisting of nothing, H, substitutedand unsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkyloxyl, substituted and unsubstituted alkenyl,substituted and unsubstituted alkynyl, substituted and unsubstitutedaryl, and substituted and unsubstituted heteroaryl groups.

In certain embodiments of the invention, a HPP/HPC having Structure L-1is prepared according to organic synthesis by reacting the parentcompounds or derivatives of the parent compounds having Structure D(e.g. acid halides, mixed anhydrides of the parent compounds, etc.):

with compounds of Structure E (Scheme 1):

T_(C)-L_(2C)-H  Structure E

wherein W_(C) is selected from the group consisting of OH, halogen,alkoxycarbonyl and substituted aryloxycarbonyloxy; and

F, L_(1C), L_(1N), L_(2C), L_(2N), L_(4C), L_(4N), T_(C) and T_(N) aredefined as supra.

In certain embodiments, a HPP/HPC having Structure L-1 is preparedfollowing Scheme 1 as described supra, wherein L_(4C) is C═O.

In certain embodiments, a parent compound having the following StructureF.

reacts with a compound having the following structure W:

to obtain a HPP/HPC of Structure L:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein:

F, L_(1C), L_(1N), L_(2C), L_(2N), L_(4C) and L_(4N) are defined assupra;

T_(N) is a transportational unit of a peptide HPP/HPC. For example,T_(N) is selected from the group consisting of Structure Na, StructureNb, Structure Nc, Structure Nd, Structure Ne, Structure Nf, StructureNg, Structure Nh, Structure Ni, Structure Nj, Structure Nk, StructureNl, Structure Nm, Structure Nn, Structure No, Structure Np, Structure Nqand Structure Nr as defined supra; and

T_(C) is selected from the group consisting of nothing, H, substitutedand unsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkyloxyl, substituted and unsubstituted alkenyl,substituted and unsubstituted alkynyl, substituted and unsubstitutedaryl, and substituted and unsubstituted heteroaryl groups.

W_(N) is selected from the group consisting of OH, halogen,alkoxycarbonyl and substituted aryloxycarbonyloxy. (Scheme 2)

In certain embodiments, a HPP/HPC having a structure of Structure L-2 isprepared by organic synthesis wherein the unwanted reactive sites suchas —COON, —NH₂, —OH, or —SH are protected before linking atransportational unit with a functional unit according to one of thesynthetic route as described supra. In certain embodiments, the obtainedprotected HPP/HPC may be further partially or completely deprotected torender a partially protected HPP/HPC or an unprotected HPP/HPCrespectively.

Preparation of Ac-Val-Pro-Asp(OEt)-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.HCl

Preparation of H-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂: 30.8 g of Z-Arg-OH wasdissolved in 500 ml of acetone. 200 ml of 20% NaOH was added into thereaction mixture. 40 g of acetic anhydride was added into the reactionmixture drop by drop. The mixture was stirred for 2 h at roomtemperature (RT). The solvent was evaporated off. The residue wasextracted with 500 ml of ethyl acetate. The ethyl acetate solution waswashed with water (3×100 ml). Ethyl acetate layer was dried over sodiumsulfate. The ethyl acetate solution was evaporated to dryness. Theresidue (Z-Arg(diAc)-OH, 30 g) was dissolved in 300 ml of acetonitrile.The mixture was cooled to 0° C. with ice-water bath. 12 g ofN,N-Diethylaminoethanol, 2 g of 4-dimethylaminopyridine, and 22 g of1,3-dicyclohexylcarbodiimide were added into the reaction mixture. Thereaction mixture was stirred for 1 hour at 0° C. and overnight at RT.The solid was removed by filtration and the solution was evaporated todryness. The residue was extracted with ethyl acetate (2×250 ml). Theethyl acetate solution was washed with 5% sodium bicarbonate (1×500 ml)and water (3×100 ml). The ethyl acetate solution was dried over sodiumsulfate. The solution was evaporated to dryness. The residue[Z-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂, 28 g] was dissolved in 300 ml ofmethanol. 2 g of 10% Pd/C was added into the solution. The mixture wasstirred for 10 h under hydrogen at RT. Pd/C was removed by filtration.The solution was evaporated to dryness to obtain 22 g ofH-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.

Preparation of Boc-Asp(OEt)-Pro-OSu: 15 g of L-proline was dissolved in300 ml of 10% sodium bicarbonate. 150 ml of acetone and 36 g ofBoc-Asp(OEt)-OSu were added into the reaction mixture. The mixture wasstirred for 5 h at RT. The mixture was washed with ether (1×300 ml). 500ml of ethyl acetate was added into the aqueous layer. The pH of themixture was adjusted to 2.4-2.5 with ice-cooled 3N HCl. The ethylacetate layer was collected and washed with water (3×300 ml). Theorganic solution was dried over sodium sulfate. The solution wasevaporated to dryness. 25 g of the residue (Boc-Asp(OEt)-Pro-OH) and 11g of N-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene.The mixture was cooled to 0° C. 16 g of 1,3-dicyclohexylcarbodiimide wasadded into the reaction mixture. The mixture was stirred for 1 hour at0° C. The solid was removed by filtration. The dichloromethylenesolution was washed with 5% sodium bicarbonate (1×200 ml) and water(3×200 ml). The organic solution was dried over sodium sulfate. Thesolution was evaporated to dryness to obtain 28 g Boc-Asp(OEt)-Pro-OSu.

Preparation of H-Asp(OEt)-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.2TFA: 22 g ofH-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂ was dissolved in 300 ml of 5% NaHCO₃. 24 gof Boc-Asp(OEt)-Pro-OSu in 150 ml of acetone was added into the reactionmixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetatewas added into the mixture. The ethyl acetate solution was washed withwater (3×100 ml). The organic solution was dried over sodium sulfate.The solution was evaporated to dryness. The residue was dissolved in 250ml of dichloromethylene. 200 ml of trifluoroacetic acid was added intothe mixture and the mixture was stirred for 30 min. The mixture wasevaporated to dryness to yield 32 g ofH-Asp(OEt)-Pro-Arg(diAc)*OCH₂CH₂N(CH₂CH₃)₂.2TFA.

Preparation of Ac-Val-Pro-OSu: 15 g of L-proline was dissolved in 300 mlof 10% sodium bicarbonate. 150 ml of acetone and 26 g of Ac-Val-OSu wereadded into the reaction mixture. The mixture was stirred for 5 h at RT.The mixture was washed with ether (1×300 ml). 500 ml of ethyl acetatewas added into the aqueous layer. The pH of the mixture was adjusted to2.4-2.5 with ice-cooled 3N HCl. The ethyl acetate layer was collectedand washed with water (3×300 ml). The organic solution was dried oversodium sulfate. The solution was evaporated to dryness. 20 g of theresidue (Ac-Val-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolvedin 300 ml of dichloromethylene. The mixture was cooled to 0° C. 16 g of1,3-dicyclohexylcarbodiimide was added into the reaction mixture. Themixture was stirred for 1 hour at 0° C. The solid was removed byfiltration. The dichloromethylene solution was washed with 5% sodiumbicarbonate (1×200 ml) and water (3×200 ml). The organic solution wasdried over sodium sulfate. The solution was evaporated to dryness toyield 20 g Ac-Val-Pro-OSu.

Preparation of Ac-Val-Pro-Asp(OEt)-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.HCl:31 g of H-Asp(OEt)-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.2TFA was dissolved in300 ml of 10% sodium bicarbonate. 150 ml of acetone and 15 g ofAc-Val-Pro-OSu were added into the reaction mixture. The mixture wasstirred for 5 h at RT. 500 ml of ethyl acetate was added into themixture. The organic layer is washed with water (3×100 ml). The ethylacetate layer was dried over sodium sulfate. Sodium sulfate was removedby filtration. 15 g of HCl gas in dioxane (200 ml) was added into thesolution. The solid was collected and washed with ether (3×50 ml). Afterdrying, 20 g of the desired product (hygroscopic product) was obtained.Elementary analysis: C₃₉H₆₆ClN₉O₁₁; MW: 872.45. Calculated % C, 53.69;H, 7.62; Cl: 4.06; N, 14.45; O: 20.17. Found % C, 53.61; H, 7.67; Cl:4.10; N, 14.40, O: 20.22. MS: m/e: 836.4; m/e+1: 836.4.

Preparation of Ac-Tyr(Ac)-Gly-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂.HCl

Preparation of H-Met-OCH₂CH₂N(CH₂CH₃)₂.TFA: 25 g of Boc-Met-OH wasdissolved in 300 ml of dichloromethylene. The mixture was cooled into 0°C. with ice-water bath. 12 g of N,N-Diethylaminoethanol, 2 g of4-dimethylaminopyridine, and 22 g of 1,3-dicyclohexylcarbodiimide wereadded into the reaction mixture. The reaction mixture was stirred for 1hour at 0° C. and overnight at RT. The solid was removed by filtrationand the dichloromethylene solution was washed with 5% sodium bicarbonate(1×500 ml) and water (3×100 ml). The ethyl acetate solution was driedover sodium sulfate. The solution was evaporated to dryness. The residue[Boc-Met-OCH₂CH₂N(CH₂CH₃)₂, 30 g] was dissolved in 250 ml ofdichloromethylene. 250 ml of trifluoroacetic acid was added into themixture and the mixture was stirred for 30 min. The solution wasevaporated to dryness to yield 26 g of H-Met-OCH₂CH₂N(CH₂CH₃)₂.TFA.

Preparation of Boc-Gly-Phe-OSu: 20 g of L-phenylalanine was dissolved in300 ml of 10% sodium bicarbonate. 150 ml of acetone and 28 g ofBoc-Gly-OSu were added into the reaction mixture. The mixture wasstirred for 5 h at RT. The mixture was washed with ether (1×300 ml). 500ml of ethyl acetate was added into the aqueous layer. The pH of themixture was adjusted to 2.4-2.5 with ice-cooled 3N HCl. The ethylacetate layer was collected and washed with water (3×300 ml). Theorganic solution was dried over sodium sulfate. The solution wasevaporated to dryness. 22 g of the residue (Boc-Gly-Phe-OH) and 10 g ofN-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene. Themixture was cooled to 0° C. 15 g of 1,3-dicyclohexylcarbodiimide wasadded into the reaction mixture. The mixture was stirred for 1 hour at0° C. The solid was removed by filtration. The dichloromethylenesolution was washed with 5% sodium bicarbonate (1×200 ml) and water(3×200 ml). The organic solution was dried over sodium sulfate. Thesolution was evaporated to dryness to yield 25 g Boc-Gly-Phe-OSu.

Preparation of H-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂.TFA: 25 g ofH-Met-OCH₂CH₂N(CH₂CH₃)₂.TFA was dissolved in 300 ml of 5% NaHCO₃. 22 gof Boc-Gly-Phe-OSu in 150 ml of acetone was added into the reactionmixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetatewas added into the mixture. The ethyl acetate solution was washed withwater (3×100 ml). The organic solution was dried over sodium sulfate.The solution was evaporated to dryness. The residue was dissolved in 250ml of dichloromethylene. 200 ml of trifluoroacetic acid was added intothe mixture and the mixture was stirred for 30 min. The mixture wasevaporated to dryness to yield 25 g ofH-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂.TFA.

Preparation of Ac-Tyr(Ac)-GIy-OSu: 11 g of L-glycine was dissolved in300 ml of 10% sodium bicarbonate. 150 ml of acetone and 36 g ofAc-Tyr(Ac)-OSu were added into the reaction mixture. The mixture wasstirred for 5 h at RT. The mixture was washed with ether (1×300 ml). 500ml of ethyl acetate was added into the aqueous layer. The pH of themixture was adjusted to 2.4-2.5 with ice-cooled 3 N HCl. The ethylacetate layer was collected and washed with water (3×300 ml). Theorganic solution was dried over sodium sulfate. The solution wasevaporated to dryness. 28 g of the residue (Ac-Tyr(Ac)-Gly-OH) and 13 gof N-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene.The mixture was cooled to 0° C. 18 g of 1,3-dicyclohexylcarbodiimide wasadded into the reaction mixture. The mixture was stirred for 1 hour at0° C. The solid was removed by filtration. The dichloromethylenesolution was washed with 5% sodium bicarbonate (1×200 ml) and water(3×200 ml). The organic solution was dried over sodium sulfate. Thesolution was evaporated to dryness to yield 20 g Ac-Tyr(Ac)-Gly-OSu.

Preparation of Ac-Tyr(Ac)-Gly-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂.HCl: 24 g ofH-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂.TFA was dissolved in 300 ml of 10%sodium bicarbonate. 150 ml of acetone and 15 g of Ac-Tyr(Ac)-Gly-OSuwere added into the reaction mixture. The mixture was stirred for 5 h atRT. 500 ml of ethyl acetate was added into the mixture. The organiclayer was washed with water (3×100 ml). The ethyl acetate layer wasdried over sodium sulfate. Sodium sulfate was removed by filtration. 15g of HCl gas in dioxane (200 ml) was added into the solution. The solidwas collected and washed with ether (3×50 ml). After drying, 18 g of thedesired product (hygroscopic product) was obtained. Elementary analysis:C₃₇H₅₃ClN₆O₉S; MW: 793.37. Calculated % C, 56.01; H, 6.73; CI: 4.47; N,10.59; O: 18.15; S: 4.04. Found C, 55.96; H, 6.76; Cl: 4.52; N, 10.54,O: 18.19; S: 4.03. MS: m/e: 757.4; m/e+1: 758.4.

Preparation of Ac-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.HCl

Preparation of Boc-Gly-Pro-OSu: 15 g of L-proline was dissolved in 300ml of 10% sodium bicarbonate. 150 ml of acetone and 27.2 g ofBoc-Gly-OSu were added into the reaction mixture. The mixture wasstirred for 5 h at RT. The mixture was washed with ether (1×300 ml). 500ml of ethyl acetate was added into the aqueous layer. The pH of themixture was adjusted to 2.4-2.5 with ice-cooled 3 N HCl. The ethylacetate layer was collected and washed with water (3×300 ml). Theorganic solution was dried over sodium sulfate. The solution wasevaporated to dryness. 21 g of the residue (Boc-Gly-Pro-OH) and 11 g ofN-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene. Themixture was cooled to 0° C. 17 g of 1,3-dicyclohexylcarbodiimide wasadded into the reaction mixture. The mixture was stirred for 1 hour at0° C. The solid was removed by filtration. The dichloromethylenesolution was washed with 5% sodium bicarbonate (1×200 ml) and water(3×200 ml). The organic solution was dried over sodium sulfate. Thesolution was evaporated to dryness to yield 23 g Boc-Gly-Pro-OSu.

Preparation of H-Gly-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.2TFA: 22 g ofH-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂ was dissolved in 300 ml of 5% NaHCO₃. 20 gof Boc-Gly-Pro-OSu in 150 ml of acetone was added into the reactionmixture. The mixture was stirred for 5 h at RT. 500 ml of ethyl acetatewas added into the mixture. The ethyl acetate solution was washed withwater (3×100 ml). The organic solution was dried over sodium sulfate.The solution was evaporated to dryness. The residue was dissolved in 250ml of dichloromethylene. 200 ml of trifluoroacetic acid was added intothe mixture and the mixture was stirred for 30 min. The mixture wasevaporated to dryness to yield 28 g ofH-Gly-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.2TFA.

Preparation of Ac-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.HCl: 26 gof H-Gly-Pro-Arg(diAc)-OCH₂CH₂N(CH₂CH₃)₂.2TFA was dissolved in 300 ml of10% sodium bicarbonate. 150 ml of acetone and 15 g of Ac-Val-Pro-OSuwere added into the reaction mixture. The mixture was stirred for 5 h atRT. 500 ml of ethyl acetate was added into the mixture. The organiclayer was washed with water (3×100 ml). The ethyl acetate layer wasdried over sodium sulfate. Sodium sulfate was removed by filtration. 15g of HCl gas in dioxane (200 ml) was added into the solution. The solidwas collected, washed with ether (3×50 ml) and dried to obtain yielded18 g of the desired product (hygroscopic product). Elementary analysis:C₃₅H₆₀ClN₉O₉; MW: 786.36. Calculated % C, 53.46; H, 7.69; Cl: 4.51; N,16.03; O: 18.31. Found % C, 53.43; H, 7.73; Cl: 4.55; N, 16.01, O:18.29. MS: m/e: 750.4; m/e+1: 751.4.

Preparation ofCyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH₂CH₂N(CH₂CH₃)₂.HCl.

Preparation of Ac-Nle-Asp(OFm)-OH: 43 g of H-Asp(OFm)-OH.TFA and 27 g ofAc-Nle-OSu were suspended in 300 ml of acetone. 300 ml of 5% NaHCO₃ wasadded into the reaction mixture. The mixture was stirred for overnightat RT. The mixture was washed with ether (1×300 ml). 500 ml of ethylacetate was added into the aqueous layer. The pH of the mixture wasadjusted to 2.4-2.5 with ice-cooled 3 N HCl. The ethyl acetate layer wascollected and washed with water (3×300 ml). The organic solution wasdried over sodium sulfate. The solution was evaporated to dryness toyield 42 g of Ac-Nle-Asp(OFm)-OH.

Preparation of Fmoc-Trp-Lys(4-Pyoc)-OH: H-Lys(4-Pyoc)-OH was preparedaccording to reference (H. Kunz and S. Birnbach, Tetrahedron Lett., 25,3567, 1984; H. Kunz and R. Barthels, Angew. Chem., Int. Ed. Engl., 22,783, 1983). 33 g of H-Lys(4-Pyoc)-OH was suspended in 300 ml of 5%NaHCO₃. 300 ml of acetone and 52 g of Fmoc-Trp-OSu were added into thereaction mixture. The mixture was stirred for overnight at RT. Themixture was washed with ether (1×500 ml). 500 ml of ethyl acetate wasadded into the mixture and the pH of the mixture was adjusted to 2.2-2.3with 3 N HCl. The ethyl acetate layer was collected and washed withwater. The organic solution was dried over sodium sulfate. The organicsolution was evaporated to dryness to yield 55 g ofFmoc-Trp-Lys(4-Pyoc)-OH.

Preparation of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OH: 100 gof Wang resin was suspended in 700 ml of DMF Solution containing 50 g ofFmoc-Trp-Lys(4-Pyoc)-OH, 13 g of 1-Hydroxybenzotriazole, 2 g of4-dimethylaminopyridine, and 12 g of N,N′-diisopropylcarbodiimide. Themixture was stirred overnight at RT. The resin was collected byfiltration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). 700 ml of 20% piperidine was added intothe resin. The mixture was stirred for 30 min. The resin was collectedby filtration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). 700 ml of DMF, 48 g of Fmoc-Arg(diAc)-OH,13 g of 1-Hydroxybenzotriazole, 35 ml of triethylamine, and 38 g ofO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium were added into theresin. The mixture was stirred for 2 hours at RT. The resin wascollected by filtration and washed with DMF (3×400 ml), methanol (3×400ml), and dichloromethylene (3×400 ml). 700 ml of 20% piperidine wasadded into the resin. The mixture was stirred for 30 min. The resin wascollected by filtration and washed with DMF (3×400 ml), methanol (3×400ml), and dichloromethylene (3×400 ml). 700 ml of DMF, 39 g ofFmoc-Phe-OH, 13 g of 1-Hydroxybenzotriazole, 35 ml of triethylamine, and38 g of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium were addedinto the resin. The mixture was stirred for 2 hours at RT. The resin wascollected by filtration and washed with DMF (3×400 ml), methanol (3×400ml), and dichloromethylene (3×400 ml). 700 ml of 20% piperidine wasadded into the resin. The mixture was stirred for 30 min. The resin wascollected by filtration and washed with DMF (3×400 ml), methanol (3×400ml), and dichloromethylene (3×400 ml). 700 ml of DMF, 60 g ofFmoc-His(Fmoc)-OH, 13 g of 1-Hydroxybenzotriazole, 35 ml oftriethylamine, and 38 g ofO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium were added into theresin. The mixture was stirred 2 hours at RT. The resin was collected byfiltration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). 700 ml of 20% piperidine was added intothe resin. The mixture was stirred for 30 min. The resin was collectedby filtration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). 700 ml of DMF, 60 g of Ac-Nle-Asp(OFm)-OH,13 g of 1-Hydroxybenzotriazole, 35 ml of triethylamine, and 38 g ofO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium were added into theresin. The mixture was stirred 2 hours at RT. The resin was collected byfiltration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). The peptided resin was suspended in 700 mlof DMF. 50 g of MeI was added into the reaction mixture. The mixture wasstirred for 1 h at RT and 1 h at 50° C. The resin was collected byfiltration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). 700 ml of 30% piperidine was added intothe resin. The mixture was stirred for 60 min. The resin was collectedby filtration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). 700 ml of DMF, 13 g of1-Hydroxybenzotriazole, 35 ml of triethylamine, and 38 g ofO-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium were added into theresin. The mixture was stirred 10 hours at RT. The resin was collectedby filtration and washed with DMF (3×400 ml), methanol (3×400 ml), anddichloromethylene (3×400 ml). 500 ml of trifluoroacetic acid was addedinto the resin and the mixture was stirred for 1 hour at RT. The resinwas removed by filtration and the solution was evaporated to dryness.The residue was washed with ether (3×100 ml).

Preparation ofCyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH₂CH₂N(CH₂CH₃).HCl: 10g of Cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OH was dissolved in300 ml of DMF. The mixture was cooled into 0° C. with ice-water bath. 12g of N,N-Diethylaminoethanol, 2 g of 4-dimethylaminopyridine, and 22 gof 1,3-dicyclohexylcarbodiimide were added into the reaction mixture.The reaction mixture was stirred for 1 hour at 0° C. and overnight atRT. The solid was removed by filtration and the dichloromethylenesolution was washed with 5% sodium bicarbonate (1×500 ml) and water(3×100 ml). The ethyl acetate solution was dried over sodium sulfate. 2g of HCl in dioxane (20 ml) was added into the solution. The solid wascollected and washed with ether (3×30 ml). Yield was 8 g of the finalproduct.

Solid-Phase Synthesis of Peptide HPP/HPC

A peptide HPP/HPC of a peptide is prepared using trityl chloride resinand 2-(4-nitrophenylsulfonyl)ethyl group as the carboxylic groupprotecting group (Scheme 3), wherein:

is resin;

-   -   X¹ is selected from the group consisting of H, Cl, methyl, and        methoxyl;    -   R¹, R², . . . R^(n) are side chains of amino acids of the        peptide HPP/HPC numbered 1, 2, . . . n respectively from the        N-terminal to C-terminal;    -   coupling reagents are selected from the group consisting of        HBTU/DIPEA/HOBt, TBTU/DIPEA/HOBt, BOP/DIPEA/HOBt,        HATU/DIPEA/HOBt, DIC/HOB, and combinations thereof; and    -   R_(T) is selected from the group consisting of substituted and        unsubstituted alkyl, substituted and unsubstituted cycloalkyl,        substituted and unsubstituted heterocycloalkyl, substituted and        unsubstituted alkyloxyl, substituted and unsubstituted alkenyl,        substituted and unsubstituted alkynyl, substituted and        unsubstituted aryl, substituted and unsubstituted heteroaryl        groups, and a transportational unit selected from the group        consisting of Structure Na, Structure Nb, Structure Nc,        Structure Nd, Structure Ne, Structure Nf, Structure Ng,        Structure Nh, Structure Ni, Structure Nj, Structure Nk,        Structure Nl, Structure Nm, Structure Nn, Structure No,        Structure Np, Structure Nq and Structure Nr as defined supra.

As used herein, unless defined otherwise “DCM” means dichloromethane.

In certain embodiments, a peptide HPP/HPC is prepared using tritylchloride resin and 9-fluorenylmethyl group as the carboxylic groupprotecting group (Scheme 4), wherein,

X¹, R¹, R², . . . R^(n), R_(T), and coupling reagents are defined thesame as supra.

In certain embodiments, a peptide HPP/HPC is prepared using carbonateester resin and 9-fluorenylmethyl group as the carboxylic groupprotecting group (Scheme 5), wherein,

R¹, R², . . . R^(n), R_(T), and coupling reagents are defined the sameas supra.

In certain embodiments, a peptide HPP/HPC is prepared using carbonateester resin and 2-(4-nitrophenylsulfonyl)ethyl group as the carboxylicgroup protecting group (Scheme 6), wherein,

R¹, R², . . . R^(n), R_(T), and coupling reagents are defined the sameas supra.

Example 2 Peptide Hpps/Hpcs Showed Higher In Vitro Penetration RatesAcross Human Skin Comparing to their Parent Drugs

The penetration rates of HPPs/HPCs and their parent drugs through humanskin were measured in vitro by modified Franz cells. The Franz cells hadtwo chambers, the top sample chamber and the bottom receiving chamber.The human skin tissue (360-400 p.m thick) that separated the top and thereceiving chambers was isolated from the anterior or posterior thighareas.

A compound tested (2 mL, 20% in 0.2 M phosphate buffer, pH 7.4) wasadded to the sample chamber of a Franz cell. The receiving chambercontains 10 ml of pH 7.4 phosphate buffer (0.2 M) which was stirred at600 rpm. The amount of the tested compound penetrating the skin wasdetermined by high-performance liquid chromatography (HPLC) method. Theresults were shown in FIG. 2. The apparent flux values of the testedcompounds were calculated from the slopes in the FIG. 2 and summarizedin Table 1 respectively.

Because the lowest detectable apparent flux values in this method was 1μg/cm²/h, parent drugs that showed an apparent flux value equal to orless than 1 μg/cm²/h were considered as not detectable for penetratingacross the skin tissue. The HPPs/HPCs of these parent drugs (e.g.enterostatins, Val-Pro-Gly-Pro-Arg (VPGPR), Melanocortin II(cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH), opioid peptides (e.g.Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH) were 1 μg /cm²/h, thereforethey were not detectable for penetrating across the skin tissue.However, their HPPs/HPCs had detectable apparent flux value. Thereforethe peptide HPPs/HPCs showed a higher penetration rate (340-600 timeshigher) across the skin tissue comparing to their parent compounds.

TABLE 1 In vitro Penetration Rate of HPPs/HPCs and their ParentCompounds (I) mg/ Parent mg/ HPP/HPC cm²/h compound cm²/hAc-Tyr(Ac)-Gly-Gly-Phe-Met- 0.52 Ac-Tyr-Gly-Gly- 0.001OCH₂CH₂N(CH₂CH₃)₂•HCl Phe-Met-OH HCl•(CH₃)₂NCH₂CH₂CH₂CO-Tyr(Ac)- 0.55Ac-Tyr-Gly-Gly- 0.001 Gly-Gly-Phe-Met-OCH₂CH₂CH₂CH₃ Phe-Met-OHcyclo(1,6)-Ac-Nle-Asp-His-Phe- 0.46 cyclo(1,6)-Ac- 0.001Arg(diAc)-Trp-Lys- Nle-Asp-His-Phe- OCH₂CH₂N(CH₂CH₃)₂•HCl Arg-Trp-Lys-OHcyclo(1,6)-H-Nle-Asp-His-D-Phe(4-I)- 0.34 cyclo(1,6)-Ac- 0.001Arg(Ac)-Trp-Lys-NH₂•HCl, Nle-Asp-His-D- Phe(4-I)-Arg-Trp- Lys-NH₂cyclo(1,6)-H-Nle-Asp-His-D-Ala(2- 0.50naphthyl)-Arg(NO₂)-Trp-Lys-NH₂•HCl Ac-Val-Pro-Gly-Pro-Arg(diAc)- 0.60H-Val-Pro-Gly- 0.001 OCH₂CH₂N(CH₂CH₃)₂•HCl Pro-Arg-OH

Example 3 Conversion of HPPs/HPCs to Their Parent Drugs

Peptide HPPs/HPCs converted to the parent peptides or peptide-relatedcompounds quickly in good yield in human plasma.

A peptide HPP/HPC (20 mg) was incubated with whole blood (1 mL) for 30min at 37° C. and analyzed by HPLC. The results showed that most of thepeptide HPPs/HPCs converted back to the parent peptides orpeptide-related compounds (Table 2).

TABLE 2 Hydrolysis product analysis of peptide HPPs/HPCs in plasmaHydrolysis products Amount A) Hydrolysis of Ac-Tyr(Ac)-Gly-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂•HCl Peptide HPP/HPC  3%Ac-Tyr-Gly-Gly-Phe-Met-OCH₂CH₂N(CH₂CH₃)₂•HCl,  2%Ac-Tyr-Gly-Gly-Phe-Met-OH  8% Parent drug 60% other side products (aminoacids, dipeptides, tripeptides, 27% tetrapeptides) B) Hydrolysis ofHCl•(CH₃)₂NCH₂CH₂CH₂CO-Tyr(Ac)-Gly-Gly-Phe- Met-OCH₂CH₂CH₂CH₃, PeptideHPP/HPC  5% (CH₃)₂NCH₂CH₂CH₂CO-Tyr-Gly-Gly-Phe-Met-  6% OCH₂CH₂CH₂CH₃(CH₃)₂NCH₂CH₂CH₂CO-Tyr-Gly-Gly-Phe-Met-OH 10% Parent drug 55% other sideproducts (amino acids, dipeptides, tripeptides, 24% tetrapeptides) C)Hydrolysis of cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH₂CH₂N(CH₂CH₃)₂•HCl Peptide HPP/HPC  4%cyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(Ac)-Trp-Lys-  8%OCH₂CH₂N(CH₂CH₃)₂•HCl, cyclo(1,6)-Nle-Asp-His-Phe-Arg-Trp-Lys-OH 10%Parent drug 45% other side products (amino acids, dipeptides,tripeptides, 33% tetrapeptides)

Example 4 Treatment of Obesity using Peptide HPPs/HPCs

Enterostatins [Val-Pro-Asp-Pro-Arg (VP DPR), Val-Pro-Gly-Pro-Arg(VPGPR), and Ala-Pro-Gly-Pro-Arg (APGPR)] are pentapeptides derived fromthe NH₂-terminus of procolipase after tryptic cleavage and belong to thefamily of gut-brain peptides. They regulate fat intake and may be usedfor the treatment of obesity (Erlanson-Albertsson C, York D, Obes. Rev.1997 July; 5(4): 360-72 and Sorhede M, Mei J, Erlanson-Albertsson C., J.Physiol. 87:273-275, 1993). H-Val-Pro-Asp-Pro-Arg-OH produced adose-dependent reduction in food intake when injected intraperitoneallyinto Osborne-Mendel rats that had been starved overnight. Thisinhibition of feeding was observed when the rats were fed a high-fatdiet but not in rats fed a high-carbohydrate, low-fat diet (Okada S. etal. Physiol Behay., 1991 June; 49(6): 1185-9).

Anti-Obesity Activity of H-Val-Pro-Gly-Pro-Arg(NO₂)—OCH(CH₃)₂.HCl inSprague Dawley Rats and DB/DB Mice.

H-Val-Pro-Gly-Pro-Arg(NO₂)—OCH(CH₃)₂.HCl (administrated transdermally,as low as 0.3 mg/kg in rat) reduced food intakes and body weights inSprague Dawley rats (SD rats) and DB/DB mice. Results were shown inTables 3, 4 and 5.

In a first experiment, 40 female Sprague Dawley rats (15 weeks old,318-346 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Val-Pro-Gly-Pro-Arg(NO₂)—OCH(CH₃)₂.HCl in 0.2 ml of water wasadministered transdermally to the back of rat (n=10) twice per day for30 days respectively. The results showed thatH-Val-Pro-Gly-Pro-Arg(NO₂)—OCH(CH₃)₂.HCl reduced body weights of ratseffectively (Table 3).

TABLE 3 Anti-obese activity of H-Val-Pro-Gly-Pro-Arg(NO₂)- OCH(CH₃)₂•HClin Sprague Dawley rats. Group Weight (g) Food intake Weight (g) (dosage)(Day 1) (per day & per rat) (Day 30) A (0 mg/kg) 331.5 ± 6.3 24.0 ± 2.5361.2 ± 6.1 B (10 mg/kg) 331.7 ± 6.2 19.9 ± 2.9 308.4 ± 4.5 C (1 mg/kg)333.1 ± 5.1 21.1 ± 2.7 313.7 ± 5.1 D (0.3 mg/kg) 335.4 ± 5.2 22.1 ± 2.5322.1 ± 4.3

In a second experiment, 40 young female Sprague Dawley (SD) rats(180-225 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Val-Pro-Gly-Pro-Arg(NO₂)—OCH(CH₃)₂.HCl in 0.2 ml of water wereadministered transdermally to the backs of rats (n=10) twice per day for30 days respectively. The results showed thatH-Val-Pro-Gly-Pro-Arg(NO₂)—OCH(CH₃)₂.HCl controlled overweight of youngrats effectively (Table 4).

TABLE 4 Anti-obese activity of H-Val-Pro-Gly-Pro-Arg(NO₂)- OCH(CH₃)₂•HClin Sprague Dawley rats. Group Weight (g) Food intake Weight (g) (dosage)(Day 1) (per day & per rat) (Day 30) A (0 mg/kg) 192.1 ± 5.6 24.8 ± 2.2354.1 ± 6.2 B (10 mg/kg) 192.7 ± 6.2 19.8 ± 3.3 307.4 ± 5.7 C (1 mg/kg)191.6 ± 4.7 20.1 ± 2.8 323.1 ± 4.5 D (0.3 mg/kg) 195.1 ± 5.5 21.8 ± 2.7327.2 ± 3.8

In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB mice, 16weeks old, 55-60 g) were divided into 4 groups. In group A, 0.1 ml ofwater was administered to the back of mouse (n=10) twice per day for 30days. In Groups B, C, and D, 15 mg/kg, 1.5 mg/kg, and 0.5 mg/kg ofH-Val-Pro-Gly-Pro-Arg(NO₂)- OCH(CH₃)₂•HCl in 0.1 ml of water wasadministered transdermally to the back of mouse (n=10) twice per day for30 days respectively. The results showed thatH-Val-Pro-Gly-Pro-Arg(NO₂)-OCH(CH₃)₂•HCl reduced body weights and bloodglucose levels of obese mice effectively (Table 5).

TABLE 5 Anti-obese activity of H-Val-Pro-Gly-Pro-Arg(NO₂)- OCH(CH₃)₂•HClin obese mice (SLAC/DB/DB). Blood Glucose Blood Glucose Levels (day 1)Levels (day 30) Group Weight (g) (mg/dL, no Weight (g) (mg/dL, no(dosage) (Day 1) fasting) (Day 30) fasting) A(0 mg/kg) 56.7 ± 2.3 190.4± 27.2 66.5 ± 4.2 259.4 ± 35.1 B(15 mg/kg) 57.7 ± 1.6 206.4 ± 21.8 52.1± 2.2 137.4 ± 25.2 C(1.5 mg/kg) 57.2 ± 2.1 201.4 ± 23.1 52.3 ± 1.9 142.4± 18.7 B(0.5 mg/kg) 56.2 ± 2.7 199.7 ± 26.8 54.2 ± 2.9 153.4 ± 26.4

Anti-obesity of H-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃.HCl in SpragueDawley Rats

H-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃.HCl (administratedtransdermally, as low as 0.3 mg/kg in rat) reduced food intakes and bodyweights in SD rats and DB/DB mice. Results were shown in Tables 6, 7,and 8.

In a first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old,315-340 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃.HCl in 0.2 ml of water wasadministered transdermally to the back of rat (n=10) twice per day for30 days respectively. The results showed thatH-Val-Pro-Gly-Pro-Arg(diAc)OCH₂CH₂CH₂CH₃.HCl reduced body weights ofrats effectively (Table 6).

TABLE 6 Anti-obese activity of H-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃•HCl in Sprague Dawley rats. Group Weight (g) Food intakeWeight (g) (dosage) (Day 1) (per day & per rat) (Day 30) A (0 mg/kg)327.5 ± 8.7 24.1 ± 2.2 361.5 ± 5.9 B (10 mg/kg) 334.1 ± 7.5 20.9 ± 2.2329.2 ± 4.8 C (1 mg/kg) 331.6 ± 6.6 21.9 ± 1.9 336.7 ± 5.6 D (0.3 mg/kg)333.1 ± 6.1 23.0 ± 1.7 347.1 ± 5.7

In a second experiment, 40 young female Sprague Dawley (SD) rats(180-230 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃.HCl in 0.2 ml of water wereadministered transdermally to the backs of rats (n=10) twice per day for30 days. The results showed thatH-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃.HCl controlled overweight ofyoung rats effectively (Table 7).

TABLE 7 Anti-obese activity of H H-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃•HCl in Sprague Dawley rats. Group Weight (g) Food intakeWeight (g) (dosage) (Day 1) (per day & per rat) (Day 30) A (0 mg/kg)188.5 ± 5.8 24.5 ± 2.9 358.9 ± 8.1 B (10 mg/kg) 191.7 ± 4.6 20.8 ± 2.8317.4 ± 6.4 C (1 mg/kg) 190.6 ± 5.7 22.1 ± 2.8 334.1 ± 4.9 D (0.3 mg/kg)191.1 ± 4.8 23.7 ± 2.9 346.2 ± 4.8

In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB) mice (16weeks old, 55-60 g) were divided into 4 groups. In group A, 0.1 ml ofwater was administered to the back of mouse (n=10) twice per day for 30days. In Groups B, C, and D, 15 mg/kg, 1.5 mg/kg, and 0.5 mg/kg ofH-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃.HCl in 0.1 ml of water wasadministered transdermally to the back of mouse (n=10) twice per day for30 days respectively. The results showed thatH-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃.HCl reduced body weights andblood glucose levels of obese mice effectively (Table 8).

TABLE 8 Anti-obese activity of H-Val-Pro-Gly-Pro-Arg(diAc)-OCH₂CH₂CH₂CH₃•HCl in obese mice (SLAC/DB/DB). Blood Glucose BloodGlucose Levels (day 1) Levels (day 30) Group Weight (g) (mg/dL, noWeight (g) (mg/dL, no (dosage) (Day 1) fasting) (Day 30) fasting) A(0mg/kg) 57.3 ± 2.7 197.3 ± 30.8 69.3 ± 4.7 256.7 ± 45.9 B(15 mg/kg) 56.7± 2.7 201.5 ± 24.6 54.7 ± 3.8 152.4 ± 17.9 C(1.5 mg/kg) 57.6 ± 3.8 195.4± 36.7 58.3 ± 2.9 166.4 ± 20.8 B(0.5 mg/kg) 57.9 ± 2.7 196.9 ± 29.8 59.3± 3.2 179.4 ± 21.1

Anti-Obesity of H-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₂.HCl in SpragueDawley Rats.

H-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl (administratedtransdermally, as low as 0.3 mg/kg in rat) reduced food intakes and bodyweights in SD rats and DB/DB mice. Results are shown in Tables 9, 10,and 11.

In a first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old,320-345 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl in 0.2 ml of water wasadministered transdermally to the back of rat (n=10) twice per day for30 days respectively. The results showed thatH-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl reduced body weights ofrats effectively (Table 9).

TABLE 9 Anti-obese activity of H-Ala-Pro-Gly-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl in Sprague Dawley rats. Group Weight (g) Food intakeWeight (g) (dosage) (Day 1) (per day & per rat) (Day 30) A (0 mg/kg)331.0 ± 8.5 24.3 ± 2.7 361.4 ± 5.2 B (10 mg/kg) 332.2 ± 7.4 20.8 ± 2.4315.4 ± 3.8 C (1 mg/kg) 333.6 ± 7.8 21.8 ± 2.3 323.7 ± 4.4 D (0.3 mg/kg)335.1 ± 6.2 22.7 ± 1.8 335.1 ± 4.8

In a second experiment, 40 young female Sprague Dawley (SD) rats(182-223 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl in 0.2 ml of water wasadministered transdermally to the backs of rats (n=10) twice per day for30 days respectively. The results showed thatH-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl controlled overweight ofrats effectively (Table 10).

TABLE 10 Anti-obese activity of H-Ala-Pro-Gly-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl in Sprague Dawley rats. Group Weight (g) Food intakeWeight (g) (dosage) (Day 1) (per day & per rat) (Day 30) A (0 mg/kg)191.5 ± 5.1 24.9 ± 2.6 355.5 ± 8.2 B (10 mg/kg) 193.7 ± 4.2 19.5 ± 2.3305.4 ± 4.7 C (1 mg/kg) 192.6 ± 4.1 20.3 ± 2.7 321.7 ± 4.0 D (0.3 mg/kg)194.1 ± 4.5 21.3 ± 2.2 326.2 ± 4.8

In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB) mice (16weeks old, 53-61 g) were divided into 4 groups. In group A, 0.1 ml ofwater was administered to the back of mouse (n=10) twice per day for 30days. In Groups B, C, and D, 15 mg/kg, 1.5 mg/kg, and 0.5 mg/kg ofH-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl in 0.1 ml of water wasadministered transdermally to the back of mouse (n=10) twice per day for30 days respectively. The results showed thatH-Ala-Pro-Gly-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl reduced body weights andblood glucose levels of obese mice effectively (Table 11).

TABLE 11 Anti-obese activity of H-Ala-Pro-Gly-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl in obese mice (SLAC/DB/DB). Blood Glucose BloodGlucose Levels (day 1) Levels (day 30) Group Weight (g) (mg/dL, noWeight (g) (mg/dL, no (dosage) (Day 1) fasting) (Day 30) fasting) A(0mg/kg) 56.5 ± 2.7 199.4 ± 30.7 67.8 ± 4.5 257.4 ± 38.2 B(15 mg/kg) 57.2± 2.2 202.4 ± 21.4 51.9 ± 2.7 139.5 ± 15.9 C(1.5 mg/kg) 57.1 ± 2.8 199.4± 23.7 53.3 ± 3.2 148.4 ± 16.4 B(0.5 mg/kg) 58.4 ± 2.9 197.6 ± 28.2 54.7± 2.7 159.4 ± 24.4

Anti-obesit of H-Val-Pro-Asp(OEt)-Pro-Arg(NO₂—)OCH₂CH₂CH₂CH₂.HCl inSprague Dawley Rats.

H-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl (administratedtransdermally, as low as 0.3 mg/kg in rat) reduced food intake and bodyweights in SD rats and DB/DB mice. Results were shown in Tables 12, 13,and 14.

In a first experiment, 40 female Sprague Dawley (SD) rats (15 weeks old,320-350 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl in 0.2 ml of water wasadministered transdermally to the back of rat (n=10) twice per day for30 days respectively. The results showed thatH-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)—OCH₂CH₂CH₂CH₃.HCl reduced body weightsof rats effectively (Table 12).

TABLE 12 Anti-obese activity of H-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl in Sprague Dawley rats. Group Weight (g) Food intakeWeight (g) (dosage) (Day 1) (per day & per rat) (Day 30) A (0 mg/kg)330.7 ± 7.4 24.3 ± 2.3 363.5 ± 5.9 B (10 mg/kg) 330.5 ± 8.2 20.1 ± 3.2318.1 ± 3.9 C (1 mg/kg) 329.8 ± 7.8 21.9 ± 2.7 326.8 ± 2.8 D (0.3 mg/kg)333.5 ± 7.1 22.7 ± 2.5 333.1 ± 3.9

In a second experiment, 40 young female Sprague Dawley (SD) rats(185-220 g) were divided into 4 groups. In group A, 0.2 ml of water wasadministered to the back of rat (n=10) twice per day for 30 days. InGroups B, C, and D, 10 mg/kg, 1 mg/kg, or 0.3 mg/kg ofH-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃.HCl in 0.2 ml of waterwere administered transdermally to the backs of rats (n=10) twice perday for 30 days. The results showed thatH-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃.HCl controlled overweightof rats effectively (Table 13).

TABLE 13 Anti-obese activity of H-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl in Spraque Dawley rats. Group Weight (g) Food intakeWeight (g) (dosage) (Day 1) (per day & per rat) (Day 30) A (0 mg/kg)192.3 ± 5.8 24.1 ± 2.8 357.1 ± 6.2 B (10 mg/kg) 191.2 ± 5.2 20.4 ± 2.7315.4 ± 6.7 C (1 mg/kg) 193.2 ± 4.7 21.3 ± 2.1 325.4 ± 4.9 D (0.3 mg/kg)192.1 ± 4.6 22.7 ± 2.9 336.6 ± 5.8

In a third experiment, 40 obese female DB/DB mice (SLAC/DB/DB) mice (16weeks old, 53-61 g) were divided into 4 groups. In group A, 0.1 ml ofwater was administered to the back of mouse (n=10) twice per day for 30days. In Groups B, C, and D, 15 mg/kg, 1.5 mg/kg, and 0.5 mg/kg ofH-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl in0.1 ml of water wasadministered transdermally to the back of mouse (n=10) twice per day for30 days respectively. The results showed thatH-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl reduced body weightsand blood glucose levels of obese mice effectively (Table 14).

TABLE 14 Anti-obese activity of H-Val-Pro-Asp(OEt)-Pro-Arg(NO₂)-OCH₂CH₂CH₂CH₃•HCl in obese mice (SLAC/DB/DB). Blood Glucose BloodGlucose Levels (day 1) Levels (day 30) Group Weight (g) (mg/dL, noWeight (g) (mg/dL, no (dosage) (Day 1) fasting) (Day 30) fasting) A(0mg/kg) 58.1 ± 2.9 199.4 ± 35.2 67.9 ± 5.1 259.4 ± 28.1 B(15 mg/kg) 57.9± 3.8 203.4 ± 27.4 52.4 ± 3.4 145.4 ± 25.7 C(1.5 mg/kg) 58.8 ± 3.1 203.4± 25.8 54.3 ± 2.9 152.4 ± 26.8 B(0.5 mg/kg) 58.7 ± 3.3 199.6 ± 31.5 56.7± 2.8 171.8 ± 28.4

Example 5 Treatment of Erectile Dysfunction (ED) and Female SexDysfunction with Peptide HPPs/HPCs

Melanocortin II is a cyclic lactam peptidesCyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH. It is the Palatin's(AMEX:PTN) novel drug candidate for the treatment of male and femalesexual dysfunction. First in a new class of therapies calledmelanocortin agonists, melanocortin II has shown promise in effectivelytreating erectile dysfunction (ED) and female sex dysfunction withoutthe cardiovascular effects found in ED drugs currently available.Melanocortin II works through a mechanism involving the central nervoussystem rather than directly on the vascular system. As a result, it mayoffer significant safety and efficacy benefits over currently availableproducts.

A HPP/HPC of Melanocortin II diffused through human skin in very highrate (˜0.3-0.5 mg/h/cm²), and provided almost side-effects-free methodsof treating erectile dysfunction or enhancing female sexual arousal.

2 mg/kgcyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(diAc)-Trp-Lys-OCH₂CH₂N(CH₂CH₃)₂.HCl(peptide A) in 0.2 ml of pH 7.0 phosphate buffer (0.1 M) was applied tothe back of male rats (Group A-1, 30 rats) once per day for 5 days. Thesame dosage ofcyclo(1,6)-Ac-Nle-Asp-His-Phe-Arg(NO₂)-Trp-Lys-OCH₂CH₂N(CH₂CH₃)₂.HCl(peptide B) was applied to the back of another group of male rats (GroupB-1, 30 rats). Rats of a control group were not treated with any drug.The results showed a 5 fold increase in solicitation and a 3 foldincrease in copulation for Group A-1 comparing to the negative controlgroup. 6 fold increase in solicitation and 3 fold increase in copulationfor Group B-1 in rats were observed comparing to the control group(Table 15).

2 mg/kg peptide A and peptide B in 0.2 ml of pH 7.0 phosphate buffer(0.1 M) were applied to the back of both male rats (30 rats) and femalerats (30 rates) once per day for 5 days. Rats of a control group werenot treated with any drug. The results showed a 6 fold increase insolicitation and 5 fold increase in copulation for both Group A-2 andGroup B-2 comparing to the control group (Table 15).

TABLE 15 Increased solicitation and copulation for rats treated withHPPs/HPCs of Melanocortin II Peptide Peptide Peptide Peptide Control A AB B Male rats X X X X Female rats X X Increased Solicitation 1 5 6 6 6Increased Copulation 1 3 5 3 5 X: treated with HPP/HPC (2 mg/kg in 0.2ml of pH 7.0 phosphate buffer (0.1M)) on the back once per day for 5days.

Example 6 Writhing Inhibition by HPPs/HPCs of Enkephalin and RelatedCompounds

Opioid peptides (e.g. Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH),Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH),H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)-OL, and H-Tyr-D-Ala-Gly-Phe-Leu-OH)exert morphine-like analgesic action. The number of writhings thatoccurred when mice were administered an acetic acid solutionintraperitoneally were counted, and the rate of inhibition based on thecontrol group was calculated.HCl.H-Tyr(Ac)-D-Ala-Gly-Phe-Leu-OCH₂(CH₂)₄—CH₃ (10 mg/kg, B),Ac-Tyr(Ac)-D-Ala-Gly-Phe-Leu-OCH₂CH₂N(CH₂CH₃).HCl (10 mg/kg, C), andHCl.H-Tyr(Ac)-D-Ala-Gly-Phe-Met(O)—OL (10 mg/kg, D) were administeredtransdermally to the neck of mice. 30 minutes later, acetic acidsolution was administered. The group A was the control group. Theresults were shown in Table 16.

TABLE 16 The rate of writhing inhibition by the HPPs/HPCs of enkephalinand related compounds. Group Dose (mg/kg) No. of Writhings % A 0 35.0 —B 10 8.6 75 C 10 5.2 85 D 10 3.2 91

Opioid peptides are natural peptides that are produced by animals andare not stable in biological systems. They are not addictive and theyare not only for treatment of any pain from a toothache, headache,arthritis, any other inflammatory, fever, cancer, dysmenorrhea, andacute migraine headache, but also for the treatment of drug abuse.

The Corresponding Parent Peptides of HPPs/HPCs Appeared in Examples areListed Below in Table D.

TABLE D Parent peptide of HPPs/HPCs appeared in examples SEQ ID PeptideHPP/HPC Parent drug NO. group Function Ac-Val-Pro-Asp(OEt)-Pro-Val-Pro-Asp- 10 Entero- Anti-obese Arg(diAc)- Pro-Arg statinsOCH₂CH₂N(CH₂CH₃)₂•HCl Ac-Tyr(Ac)-Gly-Gly-Phe- Tyr-Gly-Gly- 1 OpioidAnalgesic Met- Phe-Met. peptide activity OCH₂CH₂N(CH₂CH₃)₂•HCl. Met-enkephalin Ac-Val-Pro-Gly-Pro- Val-Pro-Gly- 11 Entero- Anti-obeseArg(diAc)- Pro-Arg statins OCH₂CH₂N(CH₂CH₃)₂•HClCyclo(1,6)-Ac-Nle-Asp-His- Nle-Asp-His- 9 Melanocortin melanocortinPhe-Arg(diAc)-Trp-Lys- Phe-Arg-Trp- II agonists maleOCH₂CH₂N(CH₂CH₃)₂•HCl. Lys and female sexual dysfunction

1. (canceled)
 2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled) 6.(canceled)
 7. (canceled)
 8. (canceled)
 9. A high penetration compositionhaving the following chemical structure:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein: F comprises a moiety of a peptide or a peptide-relatedcompound, having a structure of Structure F-1:

each A₁-A_(m) is independently selected from the group consisting of2-naphthylalanine, substituted and unsubstituted alkyl, substituted andunsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted alkoxyl, substituted andunsubstituted alkenyl, substituted and unsubstituted alkynyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, substituted andunsubstituted aryl, substituted and unsubstituted heteroaryl residues,Structure A and Structure B:

each p of each A₁-A_(m) is an independently selected integer; Z_(A-1) oneach carbon of each A₁-A_(m), Z_(A-2) for each A₁-A_(m), Z_(NT),Z_(CT-1) and Z_(CT-2) are independently selected from the groupconsisting of H, CH₃, C₂H₅, C₃H₇, CF₃, C₂F₅, C₃F₇, substituted andunsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkyloxyl, substituted and unsubstituted alkenyl,substituted and unsubstituted alkynyl, substituted and unsubstitutedaryl, substituted and unsubstituted heteroaryl groups, substituted andunsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide; R_(A) on each carbon of each A₁-A_(m), R_(B) on each carbon ofeach A₁-A_(m), R_(NT) and R_(CT) are selected from the group consistingof substituted and unsubstituted imidazolyl, substituted andunsubstituted quanidino, substituted and unsubstituted carboxyl,substituted and unsubstituted carboxamide, substituted and unsubstitutedalkyl, substituted and unsubstituted cycloalkyl, substituted andunsubstituted heterocycloalkyl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted alkylcarbonyl, substituted andunsubstituted perfluoroalkyl, substituted and unsubstituted alkylhalide, substituted and unsubstituted aryl, and substituted andunsubstituted heteroaryl groups; when a p of a A₁-A_(m) is an integer noless than 2, R_(A) or R_(B) on each carbon can be the same or different,Z_(A-1) on each carbon can be the same or different; an amino and ancarboxyl functional group on a peptide chain may further form lactambridges; a thiol group may further form disulfide bridges; T_(B) of eachA₁-A_(m), T_(c) and T_(N) are independently selected from the groupconsisting of nothing, H, substituted and unsubstituted alkyl,substituted and unsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted alkyloxyl, substitutedand unsubstituted alkenyl, substituted and unsubstituted alkynyl,substituted and unsubstituted aryl, substituted and unsubstitutedheteroaryl, Structure Na, Structure Nb, Structure Nc, Structure Nd,Structure Ne, Structure Nf, Structure Ng, Structure Nh, Structure Ni,Structure Nj, Structure Nk, Structure Nl, Structure Nm, Structure Nn,Structure No, Structure Np, Structure Nq, and Structure Nr:

each R₁₁-R₁₆ is independently selected from the group consisting ofnothing, H, CH₂COOR₁₁, substituted and unsubstituted alkyl, substitutedand unsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, P, NR₁₁, orany other pharmaceutically acceptable groups; L_(1B) of each A₁-A_(m),L_(1C) and L_(1N) are selected from the group consisting of nothing, O,S, —N(L₃)-, —N(L₃)—CH₂—O, —N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)—O,—S—CH(L₃)—O—; L_(2B) of each A₁-A_(m), L_(2C) and L_(2N) are selectedfrom the group consisting of nothing, O, S, —N(L₃)-, —N(L₃)—CH₂—O,—N(L₃)—CH₂—N(L₅)-, —O—CH₂—O—, —O—CH(L₃)—O, —S—CH(L₃)—O—, —O-L₃-, —N-L₃-,—S-L₃- and —N(L₃)-L₅-; L_(4B) of each A₁-A_(m), L_(4C) and L_(4N) areselected from the group consisting of nothing, C═O, C═S,

for each L_(1B), L_(1C), L_(1N), L_(2B), L_(2C), L_(2N), L_(4B), L_(4C)and L_(4N), L₃ and L₅ are independently selected from the groupconsisting of nothing, H, CH₂COOL₆, substituted and unsubstituted alkyl,substituted and unsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, P, NL₃, or anyother pharmaceutically acceptable groups; L₆ is selected from the groupconsisting of H, OH, Cl, F, Br, I, substituted and unsubstituted alkyl,substituted and unsubstituted cycloalkyl, substituted and unsubstitutedheterocycloalkyl, substituted and unsubstituted aryl, substituted andunsubstituted heteroaryl, substituted and unsubstituted alkoxyl,substituted and unsubstituted alkylthio, substituted and unsubstitutedalkylamino, substituted and unsubstituted perfluoroalkyl, andsubstituted and unsubstituted alkyl halide, wherein any carbon orhydrogen may be further independently replaced with O, S, N, P(O)OL₆,CH═CH, C═C, CHL₆, CL₆L₇, aryl, heteroaryl, or cyclic groups; L₇ isselected from the group consisting of H, OH, Cl, F, Br, I, substitutedand unsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted aryl, substituted and unsubstituted heteroaryl,substituted and unsubstituted alkoxyl, substituted and unsubstitutedalkylthio, substituted and unsubstituted alkylamino, substituted andunsubstituted perfluoroalkyl, and substituted and unsubstituted alkylhalide, wherein any carbon or hydrogen may be further independentlyreplaced with O, S, N, P(O)OL₆, CH═CH, C═C, CHL₆, CL₆L₇, aryl,heteroaryl, or cyclic groups.
 10. The high penetration composition ofclaim 9 wherein the peptides are selected from the group consisting ofenterostatins, Melanocortin II, and opioid peptides
 11. The highpenetration composition of claim 9 comprising a structure selected formthe group consisting of Structure 2, Structure 3, Structure 4, Structure5, Structure 6, Structure 7 Structure 8, Structure 9, Structure 10,Structure 11, Structure 12, Structure 13, Structure 14, Structure 15,Structure 16, Structure 17, Structure 18, Structure 19, Structure 20,Structure 21, Structure 22, Structure 23, Structure 24, Structure 25,Structure 26, Structure 27, Structure 28, Structure 29, Structure 30,Structure 31, Structure 32, Structure 33, Structure 34, Structure 35,Structure 36, Structure 37, Structure 38, Structure 39, Structure 40,Structure 41, Structure 42, Structure 43, Structure 44, Structure 45,Structure 46, Structure 47, Structure 48, Structure 49, Structure 50,Structure 51, Structure 52, Structure 53, Structure 54, Structure 55,Structure 56, Structure 57, Structure 58, Structure 59, Structure 60,Structure 61, Structure 62, Structure 63, Structure 64, Structure 65,Structure 66, Structure 67, and Structure 68, Structure 69, Structure70, Structure 71, Structure 72, Structure 73, Structure 74, Structure75, Structure 76, Structure 77, Structure 78, Structure 79, Structure80, Structure 81, Structure 82, Structure 83, Structure 84, Structure85, Structure 86, Structure 87, Structure 88, Structure 89, Structure90, Structure 91, Structure 92, Structure 93, Structure 94, Structure95, Structure 96, Structure 97, Structure 98, Structure 99, Structure100, Structure 101, Structure 102, Structure 103, Structure 104,Structure 105, Structure 106, Structure 107, Structure 108, Structure109, Structure 110, Structure 111, Structure 112, Structure 113,Structure 114, Structure 115, Structure 116, Structure 117, Structure118, Structure 119, Structure 120, Structure 121, Structure 122,Structure 123, Structure 124, Structure 125, Structure 126, Structure127, Structure 128, Structure 129, Structure 130, Structure 131,Structure 132, Structure 133, Structure 134, Structure 135, Structure136, Structure 137, Structure 138, Structure 139, Structure 140,Structure 141, Structure 142, Structure 143, Structure 144, Structure145, Structure 146, Structure 147, Structure 148, Structure 149,Structure 150, Structure 151, Structure 152, Structure 153, Structure154, Structure 155, Structure 156, Structure 157, Structure 158,Structure 159, Structure 160, Structure 161, Structure 162, Structure163, Structure 164, Structure 165, Structure 166, Structure 167,Structure 168, Structure 169, Structure 170, Structure 171, Structure172, Structure 173, Structure 174, Structure 175, Structure 176,Structure 177, Structure 178, Structure 179, Structure 180, Structure181, Structure 182, Structure 183, Structure 184, Structure 185,Structure 186, Structure 187, Structure 188, Structure 189, Structure190, Structure 191, Structure 192, Structure 193, Structure 194,Structure 195, Structure 196, Structure 197, Structure 198, Structure199, Structure 200, Structure 201, Structure 202, Structure 203,Structure 204, Structure 205, Structure 206, Structure 207, Structure208, Structure 209, Structure 210, Structure 211, Structure 212,Structure 213, Structure 214, Structure 215, Structure 216, Structure217, Structure 218, Structure 219, Structure 220, Structure 221,Structure 222, Structure 223, Structure 224, Structure 225, Structure226, Structure 227, Structure 228, Structure 229, Structure 230,Structure 231, Structure 232, Structure 233, Structure 234, Structure235, Structure 236, Structure 237, Structure 238, Structure 239,Structure 240, Structure 241, Structure 242, Structure 243, Structure244, Structure 245, Structure 246, Structure 247, Structure 248,Structure 249, Structure 250, Structure 251, Structure 252, Structure253, Structure 254, Structure 255, Structure 256, Structure 257,Structure 258, Structure 259, Structure 260, Structure 261, Structure262, Structure 263, Structure 264, Structure 265, Structure 266,Structure 267, Structure 268, Structure 269, Structure 270, Structure271, Structure 272, Structure 273, Structure 274, Structure 275,Structure 276, Structure 277, Structure 278, Structure 279, Structure280, Structure 281, Structure 282, Structure 283, Structure 284,Structure 285, Structure 286, Structure 287, Structure 288, Structure289, Structure 290, Structure 291, Structure 292, Structure 293,Structure 294, Structure 295, Structure 296, Structure 297, Structure298, Structure 299, Structure 300, Structure 301, Structure 302,Structure 303, Structure 304, Structure 305, Structure 306, Structure307, Structure 308, Structure 309, Structure 310, Structure 311,Structure 312, Structure 313, Structure 314, Structure 315, Structure316, Structure 317, Structure 318, Structure 319, Structure 320,Structure 321, Structure 322, Structure 323, Structure 324, Structure325, Structure 326, Structure 327, Structure 328, Structure 329,Structure 330, Structure 331, Structure 332, Structure 333, Structure334, Structure 335, Structure 336, Structure 337, Structure 338,Structure 339, Structure 340, Structure 341, Structure 342, Structure343, Structure 344, and Structure 345 as shown in FIG. 1, includingstereoisomers and pharmaceutically acceptable salts thereof, wherein: Ris selected from the group consisting of H, substituted andunsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkoxyl, substituted and unsubstituted alkylthio,substituted and unsubstituted alkylamino, substituted and unsubstitutedaryl, and substituted and unsubstituted heteroaryl residues; X, X₄, X₅,X₆, X₇, X₈, X₉, X₁₀, X₂₁, X₂₂, X₂₃, X₂₄, X₂₅, X₂₆, and X₂₇ areindependently selected from the group consisting of C═O, C═S, CSO, COO,CH₂OCO, COOCH₂OCO, COCH₂OCO, CH₂—O—CH(CH₂OR₄)₂, CH₂-β-CH(CH₂OCOR₄)₂,SO₂, PO(OR), NO, O, S, NR_(S), and nothing; R₁, R₂, R₄, R₅, R₆, R₇, R₈,R₉, R₁₀, R₂₁, R₂₂, R₂₃, R₂₄, R₂₅, R₂₆, and R₂₇ are independentlyselected from the group consisting of H, O, NO₂, substituted andunsubstituted alkyl, substituted and unsubstituted cycloalkyl,substituted and unsubstituted heterocycloalkyl, substituted andunsubstituted alkoxyl, substituted and unsubstituted alkylthio,substituted and unsubstituted alkylamino, substituted and unsubstitutedalkenyl, substituted and unsubstituted alkynyl, substituted andunsubstituted aryl, and substituted and unsubstituted heteroarylresidues; Ar is selected from the group consisting of phenyl,2′-naphthyl, 4-iodophenyl, substituted and unsubstituted aryl, andsubstituted and unsubstituted heteroaryl residues; and HA is selectedfrom the group consisting of nothing, hydrochloride, hydrobromide,hydroiodide, nitric acid , sulfic acid, bisulfic acid, phosphoric acid,phosphorous acid, phosphonic acid, isonicotinic acid, acetic acid,lactic acid, salicylic acid, citric acid, tartaric acid, pantothenicacid, bitartaric acid, ascorbic acid, succinic acid, maleic acid,gentisinic acid, fumaric acid, gluconic acid, glucaronic acid, saccharicacid, formic acid, benzoic acid, glutamic acid, methanesulfonic acid,ethanesulfonic acid, benzensulfonic acid, p-toluenesulfonic acid andpamoic acid.
 12. The high penetration composition of claim 9 comprisinga structure selected form the group consisting of Structure 1a,Structure 1b, Structure 1c, Structure 1d, Structure 1e, Structure 1f,Structure 1g, and Structure 1 h:

including stereoisomers and pharmaceutically acceptable salts thereof,wherein: X₄, X₅, X₆, X₇, X₈, X₉, R₄, R₅, R₆, R₇, R₈, R₉, and HA aredefined the same as in claim
 11. 13. A pharmaceutical compositioncomprising a high penetration composition according to claim 9 and apharmaceutically acceptable carrier.
 14. The pharmaceutical compositionaccording to claim 13, wherein the pharmaceutically acceptable carrieris polar.
 15. The pharmaceutical composition according to claim 13,wherein the pharmaceutically acceptable carrier is selected from thegroup of alcohol, acetone, ester, water, and aqueous solution.
 16. Amethod for penetrating a biological barrier, comprising administratingto the biological barrier a pharmaceutical composition according toclaim
 13. 17. (canceled)
 18. (canceled)
 19. (canceled)
 20. (canceled)21. (canceled)
 22. (canceled)
 23. A method for treating a condition in abiological subject, comprising administrating to the biological subjectthe high penetration composition according to claim 9 or thepharmaceutical composition according to claim
 13. 24. The methodaccording to claim 23, wherein the condition is selected from the groupconsisting of pain, injuries, inflammation related conditions,microorganism related conditions, neuropeptide related conditions,hormone related conditions, tumor, abnormal blood pressure, obesity,brain injuries, allergy, male and female sexual dysfunction, metastasis,and other conditions relating to: tuftsin. antepartum, postpartum,anti-AD activities, antidiuretic activities, calcium homeostasis,melanocyte, hormone release, platelet aggregation, activities of CNS,and phagocytosis.
 25. The method according to claim 24, wherein thehormone-related conditions are selected from the group consisting ofmenopause, bone diseases, growth hormone deficiency, hyperthyroidism,hypothyroidism, metabolism disorder conditions, abnormal blood pressure,skin condition, autoimmune disease, eye disease, preeclamptic toxemia inhigh-risk women, male and female sexual dysfunction, allergy, asthma,insomnia, depression and related conditions, cardiovascular diseases,and tumor.
 26. The method according to claim 25, wherein the bonediseases are selected from the group consisting of osteoporosis, Paget'sdisease and bone metastases.
 27. The method according to claim 25,wherein the metabolism disorder conditions are selected from the groupconsisting of obesity, abnormal blood glucose level, abnormal bloodlipid level, diabetes mellitus (type I or/and type II) anddiabetes-induced complications, including diabetic retinopathy,necrobiotic ulcers, and diabetic proteinuria.
 28. The method accordingto claim 25, wherein the abnormal blood pressure is selected from thegroup consisting of hypertension and hypotension.
 29. The methodaccording to claim 25, wherein the skin condition is selected from thegroup consisting of psoriasis and psoriatic disorders, acne, cysticacne, pus-filled or reddish bumps, comedones, papules, pustules,nodules, epidermoid cysts, keratosis pilaris, abnormal vascular skinlesions, birthmarks, moles (nevi), skin tags, scleroderma, vitiligo andrelated diseases, or aging spots (liver spots).
 30. The method accordingto claim 25, wherein the autoimmune disease is selected from the groupconsisting of discoid lupus erythematosus, systemic lupus erythematosus(SLE), autoimmune hepatitis, cleroderma, Sjogren's syndrome, rheumatoidarthritis, polymyositis, scleroderma, Hashimoto's thyroiditis, juvenilediabetes mellitus, Addison disease, vitiligo, pernicious anemia,glomerulonephritis, pulmonary fibrosis, multiple sclerosis (MS) andCrohn's disease.
 31. The method according to claim 25, wherein the eyedisease is selected from the group consisting of glaucoma, ocularhypertension, loss of vision after ophthalmic surgery, vision of awarm-blooded animal impaired by cystoid macular edema and cataract. 32.The method according to claim 25, wherein the cardiovascular diseasesare selected from the group consisting of heart attack, unstable angina,peripheral occlusive arterial disease and stroke.
 33. The methodaccording to claim 25, wherein the tumor is selected from the groupconsisting of benign tumor, breast cancer, colon-rectum cancer, oralcancer, lung or other respiratory system cancers, skin cancers, uteruscancer, pancreatic cancer, prostate cancer, genital cancer, urinaryorgans cancers, leukemia or other blood and lymph tissues cancer. 34.The method according to claim 24, wherein the microorganisms relatedcondition is selected from the group consisting of pain, injuries andinflammation related conditions.
 35. The method according to claim 34,wherein the inflammation related condition is selected from the groupconsisting of prostate gland inflammation (prostatitis),prostatocystitis, prostate enlarge fibrosis, hemorrhoids, Kawasakisyndrome, gastroenteritis, type-1 membranoproliferativeglomerulonephritis, Bartter's syndrome, chronic uveitis, ankylosingspondylitis, hemophilic arthropathy, inflamed hemorrhoids, postirradiation (factitial) proctitis, chronic ulcerative colitis,inflammatory bowel disease, cryptitis, periodontitis, arthritis, and aninflammatory condition in an organ selected from the group consisting ofliver, lung, stomach, brain, kidney, heart, ear, eye, nose, mouth,tongue, colon, pancreas, gallbladder, duodenum, rectum stomach,colonrectum, intestine, vein, respiratory system, vascular, theanorectum and pruritus ani.
 36. The method according to claim 24,wherein the neuropeptide related conditions are selected from the groupconsisting of Alzheimer's diseases and Parkinson's disease.
 37. Themethod according to claim 23, wherein the composition is administered tothe biological subject through a route selected from oral, enteral,buccal, nasal, topical, rectal, vaginal, aerosol, transmucosal,epidermal, transdermal, dermal, ophthalmic, pulmonary, subcutaneous, andparenteral administration.
 38. The method according to claim 23 whereinthe peptides is selected from the group consisting of angiotentensin,angiotensin II antagonists, angiotentensin II AT2 receptor,antimicrobial peptides, anti-oxytocin, hormones, antidiuretic hormones,adrenocorticotropic hormones, antimicrobial peptide, anti-inflammatorypeptide, bradykinin, bradykinin antagonist, endothelin peptides,endothelin peptide antagonist, gastrin, calcitonin, melanoma-associatedantigen peptide, laminin peptide, fibrinogen peptide, EAE inducingpeptides, growth factors, growth hormone releasing peotides,somatostatin, hormone releasing hormones, luteinizing hormone releasinghormone, neuropeptide, melanocyte stimulating hormones, sleep inducingpeptide, amyloid peptide, tuftsin, retro inverso-tuftsin, enterostatins,Melanocortin II, and opioid peptides and mimics.
 39. The methodaccording to claim 38 wherein the enterostatin is selected from thegroup consisting of Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg(VPGPR), and Ala-Pro-Gly-Pro-Arg (APGPR).
 40. The method according toclaim 38 wherein the opioid peptides is selected from the groupconsisting of Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-enkephalin(H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala-Gly-N-Me-Phe-Met(O)—OL, andH-Tyr-D-Ala-Gly-Phe-Leu-OH).
 41. (canceled)
 42. (canceled) 43.(canceled)
 44. (canceled)
 45. A transdermal therapeutic applicationsystem comprising a compound or composition according to claim 9, 10,11, 12 or 13 as an active substance for treating conditions treatable bya parent compound thereof, wherein the system is a spray or rub-onsolution further comprising a solvent selected from the group consistingof water, ethanol, isopropanol, acetone, DMSO, DMF, and combinationsthereof.
 46. A transdermal therapeutic application system comprising acompound or composition according to claim 9, 10, 11, 12 or 13 as anactive substance for treating conditions treatable by a parent compoundthereof, wherein the system further comprises a subject comprising anactive substance-containing matrix layer and an impermeable backinglayer.
 47. The transdermal therapeutic application system according toclaim 46, wherein the subject is a patch or a bandage.
 48. Thetransdermal therapeutic application system according to claim 46,wherein the subject is an active substance reservoir comprising apermeable bottom facing the skin, wherein by controlling the rate ofrelease, the system enables the active ingredient or a metabolite of theactive ingredient to reach constantly optimal therapeutic blood levelsto increase effectiveness and reduce the side effects of the activeingredient or a metabolite of the active ingredient.